Compound for treating or preventing LRRK2-mediated disease

Abstract

The present invention relates to a novel compound of formula (I) and a pharmaceutically acceptable salt thereof, the compound being capable of inhibiting leucine-rich repeat kinase 2 (LRRK2); and also relates to a pharmaceutical composition thereof, a preparation method therefor, and therapeutic use thereof.

Description

A compound for treating or preventing a LRRK2-mediated disease TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and specifically relates to a novel compound for inhibiting LRRK2. The present application provides the novel compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and a use for treating or preventing a LRRK2-mediated disease, including neurodegenerative diseases such as Parkinson's disease, immune inflammation-related diseases such as inflammatory bowel disease, and glaucoma, etc.

[0002] BACKGROUND

[0003] Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase encoded by the PARK8 gene, and is a member of the ROCO protein family. It is composed of 2527 amino acids (286 kDa), and contains multiple domains such as ARM, ANK, LRR, Roc, COR, Kinase, WD40, etc., wherein the Roc and COR domains jointly constitute a GTPase domain. LRRK2 is a large multifunctional protein with GTPase and serine-threonine kinase activities. Studies have shown that LRRK2 is expressed in multiple organs (including brain, kidney, lung, liver, heart and spleen, etc.), mainly exists in the cytoplasm and multiple membrane structures such as mitochondria, endosomes, lysosomes and Golgi apparatus, and is associated with multiple cell functions (including autophagy, cytoskeleton dynamics, intracellular membrane transport, synaptic vesicle circulation and inflammatory response, etc.). Abnormal pathways of LRRK2 are closely related to multiple diseases, including Parkinson's disease, glaucoma and inflammatory bowel disease, etc.

[0004] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, with a high incidence in the elderly population (1-2%), and more than 800 million patients worldwide. The main pathological features of Parkinson's disease are the degeneration and loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. Its clinical manifestations include static tremor, bradykinesia, muscle rigidity, postural imbalance and other motor symptoms, as well as sleep disorders, autonomic nervous disorders, depression and other mental symptoms, cognitive impairment and other non-motor symptoms, which seriously affect the quality of life of patients. The commonly used treatment drugs include compound dopamine preparations, dopamine receptor agonists, monoamine oxidase inhibitors, etc., which can replace and supplement the function of the continuously depleted dopamine through exogenous supplementation, enhancement of efficacy, inhibition of metabolism, etc., and can better alleviate the motor symptoms in the early stage of the disease. However, these drugs are only symptomatic and cannot stop the progression of the disease, and they are also ineffective for non-motor symptoms, and have the disadvantages of gradually increasing side effects and declining efficacy. Therefore, there is an urgent need for a disease-modifying therapy that can stop or slow down the progression of the disease. Genome-wide association studies (GWAS) have shown that LRRK2 gene mutations are one of the most common causes of familial PD, including major pathogenic mutations such as G2019S mutation. These mutations lead to overactivation of LRRK2, for example, the G2019S mutation can increase the protein kinase activity of LRRK2 by 2-3 times. In addition, several studies have also shown that idiopathic PD patients also have overactivation of LRRK2. Therefore, it is generally believed that LRRK2 inhibitors are a very promising disease-modifying therapy that can stop or slow down the progression of Parkinson's disease by inhibiting the overactivated LRRK2 kinase function. Currently, one LRRK2 inhibitor is in the phase II clinical study for the treatment of Parkinson's disease.

[0005] Glaucoma is a group of diseases that progressively damage the optic nerve and ultimately impair vision, mainly related to pathological intraocular pressure elevation. It is the second leading cause of blindness in the world, second only to cataract, and the first irreversible cause of blindness. The overall population prevalence of glaucoma is about 1%, and the incidence gradually increases with age, with more than 200 million glaucoma patients in China alone. Glaucoma-induced blindness is the result of optic nerve damage, which is closely related to elevated intraocular pressure. Therefore, reducing intraocular pressure is currently the main goal of glaucoma treatment. LRRK2 is widely distributed in TM cells, and LRRK2 inhibitors can regulate LRRK2 in TM cells and may cause TM relaxation by inhibiting the contractile tension of the actin cytoskeleton, thereby reducing intraocular pressure. Currently, one LRRK2 inhibitor is in the phase II clinical study for the treatment of glaucoma.

[0006] Inflammatory bowel disease (IBD) is a kind of idiopathic intestinal inflammatory disease involving ileum, rectum and colon. The main clinical manifestations of the disease are diarrhea, abdominal pain, hematochezia and weight loss, etc., including Crohn's disease (CD) and ulcerative colitis (UC). Ulcerative colitis is a continuous inflammation of the mucosal layer and submucosal layer of the colon, and the disease usually involves the rectum and gradually spreads to the entire colon. Crohn's disease can involve the entire digestive tract and is a non-continuous full-thickness inflammation, and the most common sites of involvement are the terminal ileum, colon and perianal region. The etiology of inflammatory bowel disease has not been fully elucidated, and it is known that the inflammatory response caused by abnormal response of the intestinal mucosal immune system plays an important role in the pathogenesis of inflammatory bowel disease. It is currently believed that this is caused by the interaction of multiple factors, mainly including environmental, genetic, infectious and immune factors, etc. Genome-wide association studies have found that LRRK2 gene is one of the main genetic loci affecting the genetic susceptibility of CD. Studies have shown that the expression of LRRK2 is up-regulated in the dendritic cells of Crohn's disease patients and the lymphoblastoid cell lines of patients carrying high-risk alleles. Analysis of mouse models shows that overexpression of LRRK2 can exacerbate colitis, which is related to Dectin-1-induced pro-inflammatory cytokine response in intestinal dendritic cells and autophagy defects. LRRK2 inhibitors can alleviate colitis, providing a new idea for the treatment of inflammatory bowel disease. Currently, LRRK2 inhibitors are in the preclinical discovery stage for the treatment of inflammatory bowel disease.

[0007] In addition, LRRK2 inhibitors are also a potential treatment for a variety of diseases, including tuberculosis, leprosy, Alzheimer's disease, dementia, Pick's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, neuroinflammation, ischemic stroke, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin disorder, type I diabetes, Sjogren's syndrome, Devic's disease, inflammatory myopathy, ankylosing spondylitis, glioblastoma, lymphoma, acute myeloid leukemia, renal cancer, breast cancer, lung cancer, prostate cancer, thyroid cancer, etc.

[0008] Therefore, LRRK2 inhibitors have broad application prospects and urgent clinical needs. At present, some related literatures and patent applications have disclosed small molecule LRRK2 inhibitors, including WO2014001973A1, WO2015092592A1, WO2016036586A1, WO2017046675A1 and WO2020247298A3, etc., but there is still an urgent need to develop more novel LRRK2 inhibitors with novel structures and better drug properties. The present application provides a novel LRRK2 inhibitor, and it is found that such compounds have good LRRK2 inhibitory activity. SUMMARY

[0009] The present application provides a LRRK2 inhibitor which can be orally taken, has high activity and good pharmacokinetic properties, has high in vivo exposure, good absorption efficiency and good brain penetration rate, and has higher drug concentration in the brain, thereby being able to exert better efficacy in the central nervous system.

[0010] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0011] wherein:

[0012] A is a five-membered heteroaryl containing 2 or 3 N atoms;

[0013] X is N or CH;

[0014] Y is selected from a single bond, O, S, NH or NRy, Ry being C 1-6 alkyl;

[0015] R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with one or more of halogen, C 1-3 alkyl, C 1-3 alkoxy or di(C 1-3 alkyl)phosphinyl;

[0016] R 2 is selected from C 1-6 alkyl, halogen, cyano, 3-7 membered aliphatic cycloalkyl or 4-8 membered aliphatic heterocyclyl, said aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, said C 1-6alkyl, 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle optionally substituted with 1, 2 or 3 R 5 substituted;

[0017] R 3 selected from cyano, C 1-6 acyl, C 1-6 alkylsulfonyl, -C(O)-NR a R b or

[0018] R a or R b each independently H or C 1-3 alkyl;

[0019] R 3a or R 3b each independently selected from H, cyano, hydroxy or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more of halo, cyano, hydroxy, alkoxy, amino; or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 1, 2 or 3 R 6 substituted, said ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O;

[0020] R 3c selected from H, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 alkylsulfonyl, C 2-6 ester, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, said 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 R 7 substituted;

[0021] R 4 selected from halo, cyano, C 1-6 alkyl or C 1-6 haloalkyl;

[0022] R 5 selected from halo, hydroxy, cyano, C 1-6 acyl or C 1-6 alkylsulfonyl;

[0023] R 6 selected from oxo, cyano, hydroxy, halo, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, -C(O)-NRaRb, C 1-6 acyl, or C 1-6 alkylsulfonyl;

[0024] R 7 selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halo, or oxo;

[0025] provided that when A contains 3 N atoms, X is CH;

[0026] when A contains 2 N atoms, X is N, R 3 is and R 3a and R 3b together with the atom to which they are attached form a ring that is optionally substituted with 1, 2, or 3 R 6 substituted, the ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, or O, and R 3c is not H or cyano.

[0027] In some specific embodiments, the compound, or a pharmaceutically acceptable salt thereof, wherein:

[0028] A is a five-membered heteroaryl containing 2 or 3 N atoms;

[0029] X is N or CH;

[0030] Y is a single bond, O, S, NH, or NRy, Rysis C 1-6 alkyl;

[0031] R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-6 membered heteroaryl, said C 3-6 cycloalkyl or 5-6 membered heteroaryl is optionally substituted with one or more of halo or C 1-3 alkyl;

[0032] R 2 is C 1-6alkyl, halo, cyano, 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, said 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle optionally substituted with 1, 2 or 3 R 5 substituted;

[0033] R 3 is cyano, C 1-6 alkyl, C 1-6 alkylsulfonyl, -C(O)-NRaRb or

[0034] each Raand Rbis independently selected from H or C 1-3 alkyl;

[0035] R 3a or R 3b is each independently selected from H, cyano, hydroxy, C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more of halo, cyano, hydroxy, alkoxy, amino; or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 1, 2 or 3 R 6 substituted, said ring is a 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O;

[0036] R 3c is H, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylsulfonyl, C 2-6 ester, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl, said 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 R 7 substituted;

[0037] R 4 is halo, cyano, C 1-6 alkyl or haloC 1-6 alkyl;

[0038] R 5 is halo, hydroxy, cyano, C 1-6 acyl or C 1-6 alkylsulfonyl;

[0039] R 6 is oxo, cyano, hydroxy, halo, amino, C 1-6 alkyl, C1-6 Haloalkyl, C 2-6 Ester group, -C(O)-NRaRb, C 1-6 Acyl or C 1-6 alkylsulfonyl;

[0040] R 7 It is cyano, C 1-6 Alkyl or oxo;

[0041] The condition is that X is CH when A contains 3 N atoms;

[0042] When A contains 2 N atoms, X is N, R 3 yes And R 3a and R 3b Together with the atoms they are connected to, they form an array of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, and in this case R 3c It is not H or cyano.

[0043] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0044] Y is a single bond, O, S, or NH;

[0045] R 1 It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, the C 3-6 cycloalkyl groups may be halogenated or C 1-3 One or more substitutions in alkyl groups;

[0046] R 2 It is C 1-3 Alkyl, halogen, cyano, 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle, wherein the aliphatic heterocycle contains one or two heteroatoms selected from N, S or O, and the 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle is optionally surrounded by one, two or three R atoms. 5 replace;

[0047] R 3 yes

[0048] R 3a or R 3b Each group is independently selected from H, cyano, hydroxyl, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3aand R 3b together with the atom to which they are both attached form an optionally substituted ring which is a 3-6 membered aliphatic ring or a 4-7 membered aliphatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, or O; 6 together with the atom to which they are both attached form an optionally substituted ring which is a 3-6 membered aliphatic ring or a 4-7 membered aliphatic heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, S, or O;

[0049] R 3c is H, cyano, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkylsulfonyl, C 2-3 ester, a 3-5 membered aliphatic ring, a 4-5 membered aliphatic heterocyclic ring, or a 5-6 membered heteroaryl group containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, said 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocyclic ring, or 5-6 membered heteroaryl group being optionally substituted with 1, 2, or 3 R 7 ;

[0050] R 4 is halogen, cyano, C 1-3 alkyl, or haloC 1-3 alkyl;

[0051] R 5 is halogen, hydroxy, cyano, formyl, acetyl, methylsulfonyl, or ethylsulfonyl;

[0052] R 6 is oxo, cyano, hydroxy, halogen, C 1-3 alkyl, C 1-3 haloalkyl, methyl ester, ethyl ester, formyl, acetyl, methylsulfonyl, or ethylsulfonyl;

[0053] R 7 is cyano, C 1-3 alkyl, or oxo.

[0054] In some specific embodiments, the compounds of formula (IIa) and (IIb) or a pharmaceutically acceptable salt thereof:

[0055] wherein R 1 , R 2 , R 3a , R 3b , R 3c , R 4 are as defined in claim 2;

[0056] More preferably, the compounds or salts thereof have the structural formula of formula (II):

[0057] wherein R 1 , R 2R 3a R 3b R 4 As defined in claim 2.

[0058] In some specific embodiments, the compound of formula (Ⅲa) or a pharmaceutically acceptable salt thereof:

[0059] Among them, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 2,

[0060] More preferably, the compound or its salt has the structural formula (III):

[0061] Among them, R 1 R 2 R 3a R 3b R 4 As defined in claim 2.

[0062] In some specific embodiments, the compound or a pharmaceutically acceptable salt thereof, wherein:

[0063] Y is NH;

[0064] R 1 Selected from C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl groups are optionally coated with halogens, C 1-3 Alkyl, C 1-3 Alkoxy or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group;

[0065] The condition is that A contains 2 N atoms, X is N, and R... 1 It is an unsubstituted ethyl group, R 2 It is a cycloalkyl group, R 3 yes R 3c When it is a triazole group, R 3a or R 3b Not both are methyl, and R 3a and R 3b It does not form a ring.

[0066] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV), Formula (V), or Formula (VI):

[0067] wherein Y, R 1 , R 2 , R 3a , R 3b , R 3c , R 4 is as defined in claim 1 or 6.

[0068] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IVa):

[0069] wherein,

[0070] R 1 is C 1-6 alkyl; R 2 is C 3-6 cycloalkyl; R 3a or R 3b each independently is C 1-6 alkyl, or R 3a and R 3b together with the atom to which they are both attached form C 3-6 cycloalkyl; R 4 is C 1-6 haloalkyl;

[0071] Preferably, R 1 is methyl or ethyl; R 2 is cyclopropyl; R 3a or R 3b is methyl, or R 3a and R 3b together with the atom to which they are both attached form cyclopropyl; R 4 is trifluoromethyl.

[0072] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Va):

[0073] wherein R 1 , R 2 , R 3a , R 3b , R 3c , R 4 is as defined in claim 7.

[0074] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, wherein:

[0075] R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, or C 1-6 cycloalkyl, said C 2-6 alkyl, C 3-6 alkenyl, C 1-3 alkynyl, or C 1-3 cycloalkyl is optionally substituted with one or more halogen, C 2 alkyl, or C 1-6 alkoxy;

[0076] R 3-6 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, or 4-8 membered aliphatic heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, S, or O; 5 substituted;

[0077] R 3a or R 3b is each independently H or C 1-6 alkyl, or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 1, 2, or 3 R 6 substituted, said ring is C 3-6 cycloalkyl or 4-8 membered aliphatic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, or O;

[0078] R 3c is C 1-6 alkyl or 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, said heteroaryl is optionally substituted with 1, 2, or 3 R 7 substituted;

[0079] R 4 is C 1-6 haloalkyl;

[0080] R 5 is halogen or cyano;

[0081] R 6 is oxo;

[0082] R 7 is C 1-6 alkyl or C 1-6 alkylthio;

[0083] Preferably,

[0084] R 1 is selected from C 1-3 alkyl, C 2-3 alkenyl or C 3-4 cycloalkyl, said C 1-3 alkyl, C 2-3 alkenyl or C 3-4 cycloalkyl is optionally substituted with one or more of halo or methoxy;

[0085] R 2 is selected from methyl, cyclopropyl, oxetane or tetrahydrofuranyl, said methyl is optionally substituted with 1 R 5 ;

[0086] R 3a or R 3b is methyl, or R 3a and R 3b together with the atom to which they are both attached form a ring optionally substituted with 2 R 6 ; 3-5 cycloalkyl or tetrahydrothienyl;

[0087] R 3c is methyl or 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N or S, said heteroaryl is optionally substituted with 1 R 7 ;

[0088] R 5 is cyano;

[0089] R 6 is oxo;

[0090] R 7 is methyl or ethylthio.

[0091] In some specific embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Vb):

[0092] wherein,

[0093] R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with one or more of C 1-3 alkyl or C 1-3 alkoxy;

[0094] R 3a or R 3b is C 1-6alkyl, or R 3a and R 3b together with the atom to which they are both attached form a C 3-5 cycloalkyl;

[0095] R 3c is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N or S;

[0096] Preferably,

[0097] R 1 is ethyl or cyclobutyl, optionally substituted with methyl or methoxy;

[0098] R 3a or R 3b is methyl, or R 3a and R 3b together with the atom to which they are both attached form a cyclopropyl group;

[0099] R 3c is

[0100] In some specific embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Via):

[0101] wherein R 1 is C 1-3 alkyl; R 8 is C 1-3 haloalkyl;

[0102] Preferably, R 1 is methyl or ethyl; R 8 is trifluoromethyl or difluoromethyl.

[0103] In some specific embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VII):

[0104] wherein,

[0105] X or X 1 are each independently N or CH;

[0106] R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl being optionally substituted with one or more halogen or di(C 1-3 alkyl)phosphinyl;

[0107] R 3a or R 3b is C 1-6 alkyl, or R 3a and R 3b together with the atom to which they are both attached form a C 3-5 cycloalkyl;

[0108] R 3c is triazolyl or tetrazolyl optionally substituted with 1 or 2 R 7 ;

[0109] R 7 each independently is C 1-3 alkyl;

[0110] Preferably, R 3c is

[0111] In some specific embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIIa) or Formula (VIIb):

[0112] wherein R 1 , R 3a , R 3b , R 3c are as defined in claim 13.

[0113] In some specific embodiments, the compound or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (VIIc) or Formula (VIId):

[0114] wherein,

[0115] R 1 is C 1-6 alkyl or C 3-6 cycloalkyl, said C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 halogen;

[0116] R 3c is triazolyl or tetrazolyl optionally substituted with 1 R 7 ;

[0117] R 7 is C 1-3 alkyl;

[0118] Preferably,

[0119] R 1 is C 1-3 alkyl or cyclopropyl optionally substituted with 1, 2 or 3 F;

[0120] R 3c is

[0121] R 7 is methyl.

[0122] In some embodiments, the compound or pharmaceutically acceptable salt thereof, wherein:

[0123] R1is ethyl or cyclopropyl;

[0124] R 3a or R 3b is methyl, or R 3a and R 3b together with the atom to which they are attached form a cyclopropyl group;

[0125] R 3c is

[0126] In another aspect, the present application provides specific compounds including, but not limited to, the following compounds:

[0127] The present application includes all pharmaceutically acceptable salt forms of the compounds. Such salts can be prepared using commercially available reagents according to conventional organic chemistry methods, and include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, nitrate, formate, acetate, succinate, benzenesulfonate, citrate, glucuronate, lactate, mesylate, tosylate, pamoate, and tartrate salts, among others.

[0128] The present application is intended to include all isotopes of atoms occurring in the present compounds. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent employed.

[0129] For stereoisomers, the compounds of the present application can have chiral centers and exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers, and the like. All such isomeric forms of these compounds are included within the scope of the present application.

[0130] In addition, certain crystal forms of the compounds of the present application can exist in multiple crystalline forms, which are also included in the present application. In addition, some of the compounds can form solvates with water or other organic solvents, and such solvates are similarly included in the scope of the present application.

[0131] In another aspect, the present application provides a process for preparing a compound of formula (I), wherein:

[0132] The compound of formula (IIa) can be synthesized by the scheme shown in the following figure.

[0133] wherein the definitions of R 3a , R 3b , R 3c , R 1 , R 2 , R 4 are as previously described.

[0134] The compound of formula (IIb) can be synthesized by the scheme shown in the following figure.

[0135] wherein the definitions of R 3a , R 3b , R 3c , R 1 , R 2 , R 4 are as previously described.

[0136] The compound of formula (II) can be synthesized by the scheme shown in the following figure.

[0137] wherein the definitions of R 3a , R 3b , R 1 , R 2 , R 4 are as previously described.

[0138] The compound of formula (IIIa) can be synthesized by the scheme shown in the following figure.

[0139] wherein the definitions of R 3a , R 3b , R 3c , R 1 , R 2 , R 4 are as previously described.

[0140] The compound of formula (III) can be synthesized by the scheme shown in the following figure.

[0141] wherein the definitions of R 3a , R 3b , R 1 , R 2 , R 4 are as previously described.

[0142] In another aspect, the present application provides pharmaceutical formulations suitable for use in human patients, comprising any of the compounds (e.g., compounds of the present application, such as compounds of Formula (I)) shown above, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulations can be used to treat or prevent a disorder or disease described herein.

[0143] In another aspect, the present application discloses the use of the compounds in the manufacture of a medicament for treating LRRK2-associated disorders. These disorders include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, Pick's disease, Lewy body dementia, dystonia, amyotrophic lateral sclerosis, neuroinflammation, progressive supranuclear palsy, and frontotemporal dementia, immune-inflammatory related diseases such as inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, Evan's syndrome, vasculitis, bullous skin disorders, type I diabetes, Sjogren's syndrome, Devic's disease, and inflammatory myopathies, as well as malignancies and glaucoma.

[0144] The compounds of the present application have LRRK2 inhibitory activity, and in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 500 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 400 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 300 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 200 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 100 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 50 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 20 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 10 nM, in some embodiments, the compounds of the present application have an IC50 value against LRRK2 kinase of less than 1 nM.

[0145] The compounds of the present application also show good in vitro liver microsomal stability and pharmacokinetic profiles in plasma, brain. One skilled in the art can employ relevant experiments known for determining such parameters. In some embodiments, the compounds of the present application exhibit low clearance (CL) and better half-life (T1 / 2), for example, as determined by the in vitro microsomal stability assay described below; in some embodiments, the compounds of the present application have better AUC and Cmax, as determined by animal in vivo PK assays commonly used in the art.max , exhibit better in vivo exposure; in some embodiments, the compounds of the application have better brain penetration, cross the blood-brain barrier more easily, and have higher brain drug concentrations as measured in animal in vivo CNS-PK tests commonly used in the art.

[0146] Terminology

[0147] Alkyl or alkane is a fully saturated straight chain or branched non-aromatic hydrocarbon. In general, unless otherwise defined, straight chain or branched alkyl groups have from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms. Examples of straight chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, pentyl and octyl. C1-C6 straight chain or branched alkyl groups are also referred to as "lower alkyl".

[0148] Also, as used throughout the specification, examples and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to alkyl moieties having substituents replacing the hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioformate, or thioacetate), alkoxyl, phosphoryl, phosphine, phosphonate, phosphinate, amino, amide, imide, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonate, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. One of skill in the art will appreciate that the moieties substituted on the hydrocarbon chain can themselves be substituted if appropriate. For example, substituted alkyl groups can include substituted and unsubstituted forms of aminos, azidos, imines, amides, phosphoryl (including phosphonates and phosphinates), sulfonate, sulfonamides, sulfamoyls, sulfonates, and silyls, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxyls, and esters), -CF3, -CN, and the like.

[0149] Cycloalkyl preferably has from 3 to 7 ring carbon atoms and can be in substituted and unsubstituted form. Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, or methylcyclopentyl. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like.

[0150] Aryl denotes a monocyclic or bicyclic, fused ring aromatic group having 5 to 10 carbon atoms, for example phenyl, 1-naphthyl or 2-naphthyl; or a partially saturated bicyclic fused ring containing a phenyl group, for example indanyl, dihydro- or tetrahydronaphthyl.

[0151] Heteroaryl denotes an aromatic radical containing at least one heteroatom selected from nitrogen, oxygen and sulfur and is monocyclic or bicyclic. Monocyclic heteroaryl includes 5- to 8-membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur and oxygen. Bicyclic heteroaryl includes 9- or 10-membered fused ring heteroaryl groups. Heteroaryl is for example pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and benzo-fused derivatives of such monocyclic heteroaryls such as indolyl, benzimidazolyl or benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl or purinyl.

[0152] In optionally substituted heteroaryl, the substituents are preferably lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, amino optionally substituted by one or two substituents selected from lower alkyl, lower alkenyl and alkylcarbonyl, halogenated lower alkyl, lower alkoxy lower alkyl, halogen or nitro.

[0153] Alkenyl contains one or more, for example two or three, double bonds and is preferably lower alkenyl, for example 1- or 2-butenyl, 1-propenyl, allyl or vinyl.

[0154] Alkynyl is preferably lower alkynyl, for example propargyl or ethynyl.

[0155] In optionally substituted alkenyl or alkynyl, the substituents are preferably lower alkyl, lower alkoxy, halogen or di(lower alkyl)amino and are attached to a saturated carbon atom of the alkenyl or alkynyl group or to an unsaturated carbon atom of the alkenyl group.

[0156] Heterocyclyl preferably denotes a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 4 to 10 atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which can be carbon- or nitrogen-attached, wherein the ring nitrogen atoms can optionally be substituted by groups selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl and acyl, and the ring carbon atoms can be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxy or oxo, unless otherwise indicated. Heterocyclyl is for example pyrrolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxolanyl or tetrahydropyranyl.

[0157] Acyl for example denotes alkylcarbonyl, cyclohexylcarbonyl, arylcarbonyl, aryl-lower alkylcarbonyl or heteroarylcarbonyl. Lower acyl is preferably lower alkylcarbonyl, in particular propionyl or acetyl.

[0158] Hydroxyalkyl means an alkyl group substituted by at least one hydroxy group, preferably hydroxy-lower alkyl, for example hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, hydroxyisopropyl.

[0159] Cyanoalkyl refers to an alkyl group that is substituted with at least one cyano group, preferably a cyano-lower alkyl group, such as cyanomethyl or cyanoethyl.

[0160] A haloalkyl group refers to an alkyl group that is substituted with at least one halogen, preferably a halogen-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0161] Halogens are fluorine, chlorine, bromine or iodine.

[0162] Lower alkoxy groups, especially methoxy, ethoxy, isopropoxy, or tert-butoxy.

[0163] Arylalkyl groups include aryl and alkyl groups as defined above, and are, for example, benzyl, 1-phenylethyl, or 2-phenylethyl.

[0164] Heteroarylalkyl groups include heteroaryl and alkyl groups as defined above, and are, for example, 2-, 3- or 4-pyridylmethyl, 1- or 2-pyrrolithylmethyl, 1-pyrazolylmethyl, 1-imidazolylmethyl, 2-(1-imidazolyl)ethyl or 3-(1-imidazolyl)propyl.

[0165] Two adjacent substituents that can form a 5- or 6-membered carbon ring or heterocycle with the atoms of an aryl or heteroaryl group are, for example, propylene, 1- or 2-oxopropylene, 1- or 2-oxapropylene, 1-oxapropylidene, methylenedioxy, difluoro-methylenedioxy, 1- or 2-azapropylene, 1- or 2-azapropylidene, 1,2- or 1,3-diaza-2-oxopropylene, butylene, 1- or 2-oxabutene, ethylenedioxy, 1- or 2-azabutene, or 1- or 2-azabutadiene, or such groups carrying other substituents as defined above.

[0166] Alicyclic compounds refer to monocyclic or polycyclic alkanes with saturated or unsaturated bonds, with saturated monocyclic alkanes being preferred, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Polycyclic alkanes can be classified into spirocyclic and bridged rings according to their bonding mechanisms.

[0167] Aliphatic heterocycles refer to monocyclic or polycyclic alkanes with saturated or unsaturated bonds containing one or more heteroatoms in addition to carbon atoms. Heteroatoms include, for example, nitrogen, oxygen, or sulfur. Detailed Implementation

[0168] Synthesis Examples

[0169] To make the objectives and technical solutions of this invention clearer, the invention is further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, specific experimental methods not mentioned in the following embodiments were performed according to conventional experimental methods.

[0170] The abbreviations used in this article have the following meanings: LCMS (Pre-HPLC) - Liquid Chromatography-Mass Spectrometry; N,N-Dimethylformamide; PE (Ethylene Ether); EA (Ethyl Acetate); DOX (Tetrahydrofuran); MeOH (Methanol); EtOH (Ethanol); ACN (Acetonitrile); DCM (Dichloromethane); DMSO (Dimethyl Sulfoxide). t BuOK Potassium tert-butoxide (LiOH) Lithium hydroxide (COCl)₂ Oxaloyl chloride (BINAP) 1,1'-Binaphthyl-2,2'-bis(diphenylphosphine) Brettphos Pd G3 Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Cs₂CO₃) Cesium carbonate (SFC) Supercritical fluid chromatography (TLC) Thin-layer chromatography (HPLC) High-performance liquid chromatography

[0171] The structures of the compounds described in the following examples were obtained by nuclear magnetic resonance spectroscopy (NMR spectroscopy). 1 Confirmation can be made using 1H-NMR or mass spectrometry (MS).

[0172] 1The instrument for H-NMR determination is a Bruker 400MHz nuclear magnetic resonance instrument, and the determination solvent is deuterated methanol (CD3OD), deuterated chloroform (CDCl3) or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS). The chemical shift (δ) is given in units of parts per million (ppm).

[0173] The instrument for mass spectrometry (MS) determination is an Agilent (ESI) mass spectrometer, model Agilent 6120B.

[0174] Thin layer chromatography (TLC) is performed using aluminum plates (20x20cm) produced by Merck, and thin layer preparation chromatography is performed using GF254 (0.4-0.5mm) silica gel plates.

[0175] The reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing agent system used includes dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The developing agent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvents or adding triethylamine, etc.).

[0176] Unless otherwise specified, the reaction temperature is room temperature (20-30°C).

[0177] The reagents used in the examples are purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., etc.

[0178] Preparation of common intermediates

[0179] Synthesis of intermediate 1 (INT1):

[0180] Step 1: In a sealed tube, add INT1-1 (500mg, 1.62mmol) and methanol (10mL), then add ethylamine in tetrahydrofuran (1.6mL, 3.25mmol, 2mol / L). After sealing the tube, heat to 80°C and stir overnight. Cool the reaction solution to room temperature, and evaporate the solvent under reduced pressure to obtain a crude product. Purify the crude product by silica gel column [eluent: petroleum ether-ethyl acetate (100:0-100:10)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound INT1 (130mg, yield: 35.6%) as a colorless oil. LC-MS (ESI, m / z): 225.3 [M+1] + .

[0181] Synthesis of intermediate 2 (INT2):

[0182] First step: To a solution of compound INT2-1 (2 g, 9.217 mmol) in tetrahydrofuran (20 mL) was added ethylamine (457.1 mg, 10.139 mmol) solution in ice bath, which was stirred at room temperature for 30 min. After completion of the reaction, diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by normal phase column (petroleum ether: ethyl acetate = 10: 1) to get colorless oil P1 (294 mg, yield 14.43%). 1 HNMR (400 MHz, CDC13) δ 8.35 (d, J = 38.1 Hz, 1H), 5.52 (s, 1H), 3.52-3.37 (m, 2H), 1.18 (d, J = 7.2 Hz, 3H).

[0183] Synthesis of intermediate 3 (INT3):

[0184] First step: In a sealed tube, compound INT3-1 (2 g, 9.22 mmol) and tetrahydrofuran (40 mL) were added, and a solution of methylamine in tetrahydrofuran (9.22 mL, 18.44 mmol, 2 mol / L) was added under ice bath, and stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure to obtain the crude product, which was purified by silica gel column [eluent: petroleum ether-tetrahydrofuran (100:0-100:5)], the eluent was collected, and the solvent was removed under reduced pressure to obtain white solid compound INT3 (800 mg, yield: 41.2%). LC-MS (ESI, m / z): 212.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 8.38 (s, 1H), 7.94 (br, 1H), 2.89 (d, J = 4.4 Hz, 3H).

[0185] Preparation 1: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)prop-2-yl)-1- cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (Compound A)

[0186] Step 1: To a solution of 1,2,3-triazole (5 g, 72.39 mmol) in N,N- dimethylformamide (100 mL) was added potassium tert-butoxide (12.2 g, 108.59 mmol) and A-1 (21.2 g, 108.59 mmol) under nitrogen protection, and it was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (200 mL) was added for quenching, and ethyl acetate (300 mL x 3) was extracted. The organic phase was washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse phase column to obtain compound A-2 (1.44 g, yield: 10.6%) in the form of light yellow oil. 1 HNMR (400 MHz, DMSO-d6) δ 7.94-7.69 (m, 2H), 4.17-4.04 (m, 2H), 1.97-1.84 (m, 6H), 1.12 (dd, J = 14.7, 7.6 Hz, 3H). LC-MS (ESI, m / z): 184 [M+H] + .

[0187] Step 2: To a solution of acetonitrile (469.2 mg, 11.43 mmol) in tetrahydrofuran (10 mL) was slowly added n-butyllithium (2.5 M, 4.6 ml, 11.43 mmol) at -78°C, and after the reaction was stirred for 1 hour, compound A-2 (1 g, 5.72 mmol) was dissolved in tetrahydrofuran (1 mL) and added to the reaction system, and stirred for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was added for quenching, and ethyl acetate (20 mL x 3) was extracted, and saturated brine (30 x 3 mL) was washed, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound A-3 (456 mg, yield: 46.9%) in the form of light yellow powder solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 4.33 (s, 2H), 1.95 (s, 6H). LCMS (ESI, m / z): 179.2 [M+H] + .

[0188] Step 3: To a solution of compound A-3 (245 mg, 1.375 mmol) in ethanol (4 mL) was added hydrochloric acid (12 M, 0.34 mL, 4.125 mmol) and compound B (448 mg, 4.125 mmol) and it was stirred at 70 °C overnight. Upon completion of the reaction, it was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 x 3 mL), dried over anhydrous sodium sulfate, filtered, concentrated and the crude was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to afford compound A-4 (189 mg, yield: 59.2%) as a light yellow oil. LCMS (ESI, m / z): 233.2 [M+H] + .

[0189] Step 4: To a solution of compound A-4 (50 mg, 0.129 mmol) in dioxane (4 mL) was added intermediate INT1 (48.3 mg, 0.215 mmol), cesium carbonate (140 mg, 0.43 mmol), palladium acetate (5 mg, 0.022 mmol) and XantPhos (25 mg, 0.043 mmol) and it was stirred at 110 °C for 3 h under nitrogen atmosphere. Upon completion of the reaction, it was filtered, washed with ethyl acetate, concentrated and the crude was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3:1) followed by preparative high performance liquid chromatography to afford compound A as a white powder. 1 H NMR (400 MHz, DMSO-d6) d 8.72 (s, 1H), 7.97 (s, 1H), 7.74 (s, 2H), 6.05 (t, J = 5.5 Hz, 1H), 5.96 (s, 1H), 5.86 (s, 1H), 3.39-3.35 (m, 1H), 3.13 (dd, J = 12.9, 6.8 Hz, 2H), 1.95 (s, 6H), 1.10 (t, J = 7.1 Hz, 3H), 0.96-0.87 (m, 4H). LCMS (ESI, m / z): 421.1 [M+H] + .

[0190] Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)prop-2-yl)-1-cyclopropyl-1H-1,2,4-triazol-5-yl)-N4- ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound B)

[0191] First step: In a reaction flask, add 1,2,3-triazole (5 g, 72.5 mmol) and N,N- dimethylformamide (50 mL), add potassium tert-butoxide (16.3 g, 145.0 mmol) under ice bath, after stirring for 1 hour, add compound B-1 (28 g, 145.0 mmol), stir at room temperature overnight. After the reaction is completed, dilute with water (250 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain compound B-2 (3.9 g, yield: 29%) as a colorless oily liquid. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 2H), 4.09 (q, J = 7.2 Hz, 2H), 1.85 (s, 6H), 1.10 (t, J = 6.8 Hz, 1H). LC-MS (ESI, m / z): 184.1 [M+1] + .

[0192] Second step: In a reaction flask, add compound B-2 (3 g, 1.64 mmol) and methanol (30 mL), water (5 mL), and finally add lithium hydroxide (78 mg, 3.27 mmol), stir at 40°C overnight. After the reaction is completed, adjust the pH to 6-7 with dilute hydrochloric acid, evaporate the solvent under reduced pressure, dissolve in dichloromethane (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain compound B-3 (2 g, yield: 80%) as a colorless oily liquid. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 2H), 1.74 (s, 6H). LC-MS (ESI, m / z): 156.3 [M+1] + .

[0193] Third step: In a reaction flask, add compound B-3 (300 mg, 1.93 mmol) and super dry dichloromethane (10 mL), 1 drop of N,N-dimethylformamide, add oxalyl chloride (491 mg, 3.87 mmol) dropwise under ice bath after argon protection, stir at room temperature for 1 hour, evaporate the solvent under reduced pressure to obtain a crude acyl chloride, which is directly used in the next step.

[0194] Add the above crude acyl chloride to super dry dichloromethane (20 mL), protect with argon, add sodium cyanamide solid (247 mg, 3.87 mmol) under ice bath, stir at room temperature for 1 hour, then the reaction is complete. The reaction solution is directly sampled and purified by silica gel column chromatography to obtain compound B-4 (300 mg, two-step yield: 86.7%) as a colorless oily liquid. 1HNMR (400 MHz, DMSO-d6) δ 7.65 (s, 2H), 1.70 (s, 6H). LC-MS (ESI, m / z): 180.1 [M+1] + .

[0195] Fourth step: In a reaction flask, add B-4 (200 mg, 1.12 mmol) and n-BuOH (5 mL), finally add cyclopropylhydrazine hydrochloride (364 mg, 3.35 mmol), stir at 110 °C overnight. After the reaction is completed, dilute with water (5 mL) and adjust the pH of the system to 7-8 with aqueous sodium carbonate solution, extract with ethyl acetate (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, then evaporate the solvent under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain compound B-5 (75 mg, yield: 28.8%) as a yellow oily liquid. 1 HNMR (400 MHz, DMSO-d6) δ 7.65 (s, 2H), 1.70 (s, 6H). LC-MS (ESI, m / z): 180.1 [M+1] + .

[0196] Fifth step: In a reaction flask, add compound B-5 (50 mg, 0.21 mmol) and super dry tetrahydrofuran (3 mL), cool to 0 °C with an ice water bath, add NaH (35 mg, 0.86 mmol, 60% wt), stir for 1 hour in an ice bath, then add intermediate N-benzyl-2-chloro-N-ethyl-5- (trifluoromethyl) pyrimidin-4-amine (68 mg, 0.21 mmol), stir at room temperature for 1 hour until the reaction is complete, then evaporate the solvent under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography to obtain compound B-6 (45 mg, yield: 41.3%) as a yellow oily liquid. LC-MS (ESI, m / z): 513.3 [M+1] + .

[0197] Sixth step: In a reaction flask, add compound B-6 (40 mg, 0.078 mmol), Pd / C (10% wt, 10 mg), Pd(OH)2(10% wt, 10 mg), ClCH2CHCl2(10 mg, 0.078 mmol) and tetrahydrofuran (5 mL), stir at room temperature overnight under a hydrogen atmosphere. After the reaction is completed, filter, evaporate the filtrate under reduced pressure to obtain a crude product, which is purified by C18 reverse phase column (eluent: water-acetonitrile), collect the eluate, evaporate acetonitrile under reduced pressure, and freeze-dry to obtain compound B as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.15 (s, 1H), 7.73 (s, 2H), 7.20 (t, J = 5.6 Hz, 1H), 3.43-3.38 (m, 1H), 3.30-3.26 (m, 2H), 1.96 (s, 6H), 0.98 (t, J = 6.8 Hz, 3H), 0.93-0.89 (m, 4H). LC-MS (ESI, m / z): 423.2 [M+1] + .

[0198] Synthesis of 2-methyl-2-(4-methyl-3-((4-(methylamino)-5- (trifluoromethyl)pyridin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile (Compound C)

[0199] First step: 4-methyl-3-nitro-1H-pyrazole (1.98 g, 15.58 mmol) was dissolved in N,N-dimethylformamide (33 mL), cesium carbonate (10.11 g, 31.16 mmol) and 2-bromo-2-methylpropionic acid methyl ester (2.84 g, 15.58 mmol) were added, heated to 50 °C and stirred overnight. The reaction was poured into water, extracted with ethyl acetate three times, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound C-2 (1.00 g, yield: 28.2%). LC-MS (ESI, m / z): 228 [M+1] + .

[0200] Second step: Compound C-2 (1.00 g, 4.40 mmol) was dissolved in tetrahydrofuran (10 mL), aqueous lithium hydroxide solution (4 M, 10 ml) was added, and then stirred at room temperature for one hour. The reaction was adjusted to be acidic with 2N dilute hydrochloric acid, extracted with ethyl acetate three times, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated to obtain white solid compound C-3 (0.80 g, yield: 85.2%). LC-MS (ESI, m / z): 214 [M+1] + .

[0201] Step 3: Compound C-3 (0.80 g, 3.75 mmol) was dissolved in dichloromethane (16 ml), and a drop of N,N-dimethylformamide was added. Oxalyl chloride (4 ml) was added dropwise under ice bath, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was concentrated and used as is. Ammonia water (10 ml) and tetrahydrofuran (10 ml) were stirred at room temperature, and the previously prepared acyl chloride was dissolved in tetrahydrofuran (10 ml) and added dropwise to the reaction solution. The mixture was stirred at room temperature for half an hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then solid compound C-4 (0.85 g, yield: 100.0%) was obtained. LC-MS (ESI, m / z): 213 [M+1] + .

[0202] Step 4: Compound C-4 (0.85 g, 4.01 mmol) was added to a single-neck flask, and phosphorus oxychloride (13 ml) was added. The mixture was stirred at 90°C for two hours under oil bath, and then the reaction solution was slowly added dropwise to warm water (150 ml). The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After concentration, brown solid compound C-5 (0.70 g, yield: 89.8%) was obtained. LC-MS (ESI, m / z): 195 [M+1] + .

[0203] Step 5: Compound C-5 (0.70 g, 3.60 mmol) was added to a single-neck flask, and iron powder (1120 mg) and ammonium chloride (1000 mg) were added. The mixture was dissolved in methanol (6 ml), tetrahydrofuran (6 ml), and water (3 ml), and stirred at room temperature for two hours. The reaction solution was diluted with methanol, and the mixture was filtered through diatomite. The filtrate was dried over anhydrous sodium sulfate and concentrated. Compound C-6 (600 mg, yield: 67.8%) was obtained by column chromatography purification of the crude product. LC-MS (ESI, m / z): 165 [M+1] + .

[0204] Step 6: Compound C-6 (50 mg, 0.30 mmol), (2-chloro-5-trifluoromethyl-pyridin-4-yl)- methylamine (64 mg, 0.30 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol), and cesium carbonate (199 mg, 0.60 mmol) were added to a single-neck flask, and dioxane (2 ml) was added. After nitrogen replacement, the mixture was stirred at 100°C for two hours under oil bath. The reaction was directly filtered, and the filtrate was purified by preparative thin layer chromatography to obtain compound C. 1HNMR(400MHz,DMSO-d6)δ8.80(s,1H),7.97(s,1H),7.71(s,1H),6.85(s,1H),6.21(q,J= 4.0Hz,1H),2.76(d,J=4.0Hz,3H),1.96(s,3H),1.93(s,6H).LC-MS(ESI,m / z):339[M+1] + .

[0205] Example 1: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propyl-2-yl)-1-cyclopropyl-1H-1,2,4-triazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 1)

[0206] Step 1: In a reaction flask, add 1,2,3-triazole (5g, 72.5mmol) and N,N-dimethylformamide (50mL), and add under ice bath conditions. t Buok (16.3 g, 145.0 mmol), stirred for 1 hour. Compound 1-1 (28 g, 145.0 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with water (250 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography to give a colorless oily liquid compound 1-2 (3.9 g, yield: 29%). LC-MS (ESI, m / z): 184.1 [M+1] + .

[0207] Step 2: In a reaction flask, add compound 1-2 (3g, 1.64mmol), methanol (30mL), and water (5mL), and finally add LiOH (78mg, 3.27mmol). Stir overnight at 40°C. After the reaction is complete, adjust the pH to 6-7 with dilute hydrochloric acid. After removing the solvent from the system under reduced pressure, dissolve the residue in dichloromethane (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain a colorless oily liquid compound 1-3 (2g, yield: 80%). LC-MS (ESI, m / z): 156.3 [M+1] + .

[0208] Step 3: In a reaction flask, add compound 1-3 (300 mg, 1.93 mmol) and ultra-dry dichloromethane (10 mL), 1 drop of N,N-dimethylformamide, and under argon protection, add oxalyl chloride (491 mg, 3.87 mmol) dropwise in an ice bath. Stir at room temperature for 1 hour, concentrate under reduced pressure to remove the solvent, and obtain crude acyl chloride, which can be used directly in the next step.

[0209] The above crude acyl chloride was added into super dry dichloromethane (20 mL) under argon protection, sodium cyanamide solid (247 mg, 3.87 mmol) was added under ice bath, after stirring at room temperature for 1 hour, the reaction was completed, the reaction solution was directly sampled and purified by silica gel column chromatography to obtain compound 1-4 (300 mg, two-step yield: 86.7%) in colorless oily liquid. LC-MS (ESI, m / z): 180.1 [M+1] + .

[0210] Fourth step: In a reaction bottle, compound 1-4 (300 mg, 1.67 mmol) and ethanol (10 mL) were added, and finally cyclopropyl hydrazine hydrochloride (55 mg, 5.02 mmol) was added, and stirred at 90°C under argon protection overnight. After the reaction was completed, water (5 mL) was added for dilution, and the system was adjusted to pH 7-8 with aqueous sodium carbonate solution, and extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 1-5 (70 mg, yield: 18%) in yellow oily liquid. LC-MS (ESI, m / z): 234.1 [M+1] + .

[0211] Fifth step: In a reaction bottle, 1-5 (70 mg, 0.3 mmol), INT-1 (67 mg, 0.3 mmol), Brettphos Pd G3 (27 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), Cs2CO3 (196 mg, 0.6 mmol) and dioxane (5 mL) were added, and stirred at 105°C under argon protection overnight. After the reaction was completed, water (10 mL) was added for dilution, and extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography, the eluate was collected, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by C18 reverse phase column, the eluate was collected, and the acetonitrile was removed under reduced pressure, and freeze-dried to obtain compound 1. 1 HNMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.74 (s, 2H), 7.12 (s, 1H), 6.33 (dd, J = 5.2 Hz, 1H), 3.56-3.52 (m, 1H), 3.13-3.10 (m, 2H), 1.98 (s, 6H), 1.08 (t, J = 6.8 Hz, 3H), 1.00-0.97 (m, 4H). LC-MS (ESI, m / z): 421.9 [M+1] + .

[0212] Example 2: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1- cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 2)

[0213] First step: Dissolve triazole (13.80 g, 200 mmol) in N,N-dimethylformamide (250 mL), add potassium carbonate (41.40 g, 300 mmol) and methyl bromoacetate (15.30 g, 100 mmol), react at 25 °C for 15 hours. Pour the reaction into water, extract with EA three times, wash the organic phase with saturated brine once, dry over anhydrous sodium sulfate, concentrate and column chromatography to obtain compound 2-2 (4.53 g, 32.13 mmol), yield 16.06%. LC-MS (ESI, m / z): 142 [M+1] + .

[0214] Second step: Dissolve methyl [1,2,3]triazol-2-yl-acetate 2-2 (1.41 g, 10.00 mmol) in tetrahydrofuran (20 mL), protect with nitrogen, cool to minus 78 degrees Celsius, slowly drop in LDA (5.0 mL, 10.00 mmol), drop for 10 minutes, add 1,3,2-dioxazolothiophene-2,2-dioxide (1.30 g, 10.50 mmol) drop for 10 minutes, warm to 0 °C for 1 hour, cool to minus 70 degrees, slowly drop in diisopropyl lithium (5.0 mL, 10.00 mmol), drop for 10 minutes, warm to 0 °C for 1 hour. Pour the reaction into water, extract with ethyl acetate three times, wash the organic phase with saturated brine once, dry over anhydrous sodium sulfate, concentrate and column chromatography to obtain compound 2-3 (0.34 g, 2.04 mmol), yield 20.36%. LC-MS (ESI, m / z): 168 [M+1] + .

[0215] Third step: Dissolve anhydrous acetonitrile (0.23 g, 5.61 mmol) in anhydrous tetrahydrofuran (10 mL), protect with nitrogen, cool to minus 78 degrees, slowly drop in tert-butyl lithium (1.12 mL, 2.80 mmol), drop for 5 minutes, slowly add a tetrahydrofuran (2 mL) solution of compound 2-3 (0.24 g, 1.44 mmol), drop for 1 hour. Pour the reaction into water, adjust the pH of the aqueous phase to 2 with dilute hydrochloric acid, extract with ethyl acetate twice, combine the organic phases, dry over anhydrous sodium sulfate, concentrate to obtain brown oily compound 2-4 (0.24 g, 1.36 mmol), yield 96%. LC-MS (ESI, m / z): 177 [M+1] + .

[0216] Fourth Step: Compound 2-4 (0.08 g, 0.45 mmol) and cyclopropylhydrazine hydrochloride (0.20 g, 1.85 mmol) were dissolved in ethanol (10 mL), concentrated hydrochloric acid (0.2 mL) was added, and the reaction was carried out at 85°C for 15 hours. The reaction solution was directly concentrated and column chromatography was performed to obtain compound 2-5 (56 mg, 0.24 mmol) at a yield of 53.33%. LC-MS (ESI, m / z): 231 [M+1] + .

[0217] Fifth Step: Compound 2-5 (50 mg, 0.22 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)- ethylamine (59 mg, 0.26 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), 1,1'-binaphthalene-2,2'- bis(diphenylphosphine) (40 mg, 0.064 mmol), sodium tert-butoxide (45 mg, 0.47 mmol) were dissolved in dioxane (5 mL), replaced with nitrogen three times, heated to 100°C, and the reaction was carried out for 6 hours. The reaction solution was directly concentrated and column chromatography was performed to obtain compound 2. 1 HNMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.62 (s, 2H), 6.05 (s, 1H), 5.22 (s, 1H), 3.37 (qd, J = 7.2, 5.2 Hz, 2H), 3.27-3.16 (m, 1H), 1.75 (s, 4H), 1.26 (s, 1H), 1.20 (d, J = 7.3 Hz, 3H), 1.15-1.08 (m, 4H). LC-MS (ESI, m / z): 420 [M+1] + .

[0218] Example 3: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4- ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 3)

[0219] First Step: Triazole 3-1 (3.33 g, 48.21 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1.38 g, 100 mmol) and 1-bromocyclobutane ethyl carbonate (9.98 g, 48.21 mmol) were added, and the reaction was carried out at 60°C for 15 hours. The reaction solution was poured into water, extracted with ethyl acetate three times, the organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain compound 3-2 (1.20 g, 6.16 mmol) at a yield of 12.8%. 1HNMR (400 MHz, CDC13) δ 7.67 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.05-2.92 (m, 4H), 2.27-1.98 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H). LC-MS (ESI, m / z): 196 [M+1] + .

[0220] Second Step: Compound 3-2 (1.15 g, 5.89 mmol) was dissolved in THF (5 mL) under nitrogen protection, and the solution was slowly added into the solution of tert-butyllithium (4.7 mL, 11.75 mmol) in THF (20 mL) at -78 °C. After 10 minutes, the reaction was slowly added into the solution of compound 3-2 (1.15 g, 5.89 mmol) in THF (5 mL) at -78 °C. After 1 hour, the reaction was directly poured into water, and extracted with ethyl acetate twice. The aqueous phase was adjusted to pH 2 with dilute hydrochloric acid, and extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, and concentrated to give brown solid compound 3-3 (1.022 g, 5.37 mmol) with a yield of 91.2%. LC-MS (ESI, m / z): 191 [M+1] + .

[0221] Third Step: Compound 3-3 (500 mg, 2.63 mmol) and cyclopropylhydrazine hydrochloride (568 mg, 5.26 mmol) were dissolved in ethanol (10 mL), and concentrated hydrochloric acid (2 mL) was added. The reaction was carried out at 80 °C for 15 hours. The reaction was directly concentrated and column chromatography was performed to give compound 3-4 (348 mg, 1.42 mmol) with a yield of 54.1%. LC-MS (ESI, m / z): 245 [M+1] + .

[0222] Fourth Step: Compound 3-4 (348 mg, 1.42 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)- ethylamine (385 mg, 1.71 mmol), Pd2(dba)3 (0.261 mg, 0.28 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (0.266 mg, 0.43 mmol), and sodium tert-butoxide (274 mg, 2.85 mmol) were dissolved in dioxane (10 mL), and the solution was replaced with nitrogen three times. The reaction was heated to 100 °C for 5 hours. The reaction was directly concentrated and column chromatography was performed to give compound 3. 1H NMR (400 MHz, CDC13) δ 8.10 (d, J = 1.0 Hz, 1H), 7.62 (s, 2H), 6.08 (s, 1H), 5.18 (s, 1H), 3.40 (qd, J = 7.2, 5.2 Hz, 2H), 3.24 (tt, J = 7.0, 3.7 Hz, 1H), 3.13 - 2.98 (m, 4H), 2.11 - 1.98 (m, 2H), 1.22 (t, J = 7.2 Hz, 6H). LC-MS (ESI, m / z): 434 [M+1] + .

[0223] Example 4: Synthesis of N2-(3-(l-(2H-l,2,3-triazol-2-yl)cyclopentyl)-l- cyclopropyl-lH-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 4)

[0224] First step: cyclopentanecarboxylic acid methyl ester (10.00 g, 78.12 mmol), N- bromosuccinimide (16.89 g, 94.83 mmol), benzoyl peroxide (1.89 g, 7.81 mmol) were dissolved in carbon tetrachloride (100 ml), reacted at 85 °C for 2 hours, cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated under reduced pressure at 45 °C to obtain compound 4-2 (14.54 g, 70.21 mmol) at a yield of 90%, which was used directly in the next step without being tested.

[0225] Second step: triazole (1.60 g, 23.19 mmol) was dissolved in N,N-dimethylformamide (15 mL), potassium carbonate (6.40 g, 46.37 mmol) and 1-bromocyclopentanecarboxylic acid methyl ester (4.50 g, 21.63 mmol) were added, and heated to 60 °C for 15 hours. The reaction liquid was poured into water, extracted with ethyl acetate three times, washed with saturated brine once, dried over anhydrous sodium sulfate, concentrated, and column chromatography was performed to obtain compound 4-3 (0.64 g, 3.28 mmol) at a yield of 14.15%. 1 H NMR (400 MHz, CDC13) δ 8.10 (d, J = 1.0 Hz, 1H), 7.62 (s, 2H), 6.08 (s, 1H), 5.18 (s, 1H), 3.40 (qd, J = 7.2, 5.2 Hz, 2H), 3.24 (tt, J = 7.0, 3.7 Hz, 1H), 3.13 - 2.98 (m, 4H), 2.11 - 1.98 (m, 2H), 1.22 (t, J = 7.2 Hz, 6H). LC-MS (ESI, m / z): 434 [M+1] + .

[0226] Step 3: Methyl 1-[1,2,3]triazol-2-yl-cyclopentanecarboxylate 4-3 (0.31 g, 1.59 mmol) was dissolved in THF (5 mL) under nitrogen and cooled to -78 °C. n-BuLi (1.30 mL, 3.25 mmol) was added slowly and the reaction was stirred for 10 min. A solution of 3-oxo-3-(1-[1,2,3]triazol-2-yl-cyclopentyl)-propionitrile 4-4 (0.47 g, 2.30 mmol) in THF (5 mL) was added slowly and the reaction was stirred for 1 h. The reaction was quenched with water and extracted with EtOAc (2x). The aqueous layer was acidified with dilute HCl and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give 4-4 (0.58 g, 2.84 mmol, 91.7% yield) as a brown oil. LC-MS (ESI, m / z): 205 [M+1] + .

[0227] Step 4: 3-oxo-3-(1-[1,2,3]triazol-2-yl-cyclopentyl)-propionitrile 4-4 (0.47 g, 2.30 mmol) and cyclopropylhydrazine hydrochloride (1.08 g, 10.00 mmol) were dissolved in EtOH (50 mL) and concentrated HCl (1 mL) was added. The reaction was heated to 80 °C for 7 h. The reaction was concentrated and purified by column chromatography to give 4-5 (0.27 mg, 1.05 mmol, 45.50% yield). LC-MS (ESI, m / z): 259 [M+1] + .

[0228] Step 5: Compound 4-5 (50 mg, 0.19 mmol), (2-chloro-5-trifluoromethyl-pyrimidin-4-yl)- ethylamine (52 mg, 0.23 mmol), Pd2(dba)3 (35 mg, 0.038 mmol), 1,1'-binaphthalene-2,2'- bis(diphenylphosphine) (36 mg, 0.058 mmol), sodium tert-butoxide (37 mg, 0.38 mmol) were dissolved in dioxane (5 mL) and purged with nitrogen three times. The reaction was heated to 100 °C for 5 h. The reaction was concentrated and purified by column chromatography to give compound 4. 1 HNMR (400 MHz, CDC13) δ 8.07 (s, 1H), 7.61 (s, 2H), 5.99 (s, 1H), 3.40 (dd, J = 7.3, 5.3 Hz, 2H), 3.24 (t, J = 3.6 Hz, 1H), 3.06 (td, J = 7.8, 4.6 Hz, 2H), 2.63 - 2.48 (m, 2H), 1.92 - 1.80 (m, 2H), 1.69 - 1.57 (m, 3H), 1.24 (d, J = 3.0 Hz, 4H), 1.16 (d, J = 1.9 Hz, 4H). LC-MS (ESI, m / z): 448 [M+1] + .

[0229] Example 5: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1- cyclopropyl-1H-1,2,4-triazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 5)

[0230] First step: Take a reaction flask, add compound 2-3 (1.44 g, 2.0 eq) dissolved in methanol (10 mL) successively, replace 3 times with nitrogen ball, stir at 0 °C for 10 min, slowly drop 30% NaOMe methanol solution (8 mL), react at 0 °C for 20 min. Then add aminoguanidine (1.12 g, 1.0 eq), stir at 0 °C for 15 min, then warm to 80 °C and react for 5 h. TLC detection shows that the reaction is complete, directly add silica gel to the sample, and the crude product is purified by normal phase flash to obtain compound 5-2 (0.60 g, yield: 45.45%, purity: 96.33%). LC-MS (ESI, m / z): 191.94 [M+H] + .

[0231] Second step: Take a reaction flask, add compound 5-2 (0.60 g, 1.0 eq), cyclopropylboronic acid (1.26 g, 4.0 eq), Cu(OAc)2 (0.22 g, 0.2 eq), 2,2'-bipyridine (0.19 g, 0.2 eq), dichloroethane (40 mL) successively, react at 75 °C for 12 h with the mouth open. TLC detection shows that the reaction is complete, filter, wash the filter cake with dichloromethane / methanol = 10 / 1 (30 mL), add silica gel to the sample, and the crude product is purified by normal phase flash to obtain compound 5-3 (0.33 g, yield: 45.8%). LC-MS (ESI, m / z): 231.98 [M+H] + .

[0232] Third step: Take a reaction flask, add compound 5-3 (0.10 g, 1.0 eq), intermediate INT1 (0.10 g, 1.0 eq), Cs2CO3 (0.28 g, 2.0 eq), Pd2(dba)3 (0.04 g, 0.1 eq), Xantphos (0.03, 0.1 eq) and dioxane (5 mL) successively, replace 3 times with nitrogen ball, react at 90 °C for 2 h in microwave. LCMS monitoring shows that the reaction is complete, cool to room temperature, and purify the crude product 0.1 g by preparative thin layer chromatography to obtain compound 5. 1H NMR (400 MHz, CDC13) δ: 9.58 (s, 1H), 8.01 (s, 1H), 7.79 (s, 2H), 7.07 (s, 1H), 6.32 (t, 1H), 3.43 (m, 1H), 3.14 (q, 2H), 1.66 (m, 4H), 1.10-1.07 (t, 3H), 0.92-0.84 (m, 4H). LC-MS (ESI, m / z): 419.97 [M+H] + .

[0233] Example 6: Synthesis of (2-(3-(2-(2H-1,2,3-triazol-2-yl)prop-2-yl)-1- cyclopropyl-1H-pyrazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)aminoethyl)dimethyl phosphine oxide (Compound 6)

[0234] First step: To a solution of 1,2,3-triazole (5 g, 72.39 mmol) in N,N- dimethylformamide (100 mL) was added potassium tert-butoxide (12.2 g, 108.59 mmol) and compound 6-1 (21.2 g, 108.59 mmol) under nitrogen protection, and it was stirred at room temperature for 2 hours under ice bath. After the reaction was completed, saturated aqueous ammonium chloride solution (200 mL) was added for quenching, and ethyl acetate (300 mL x 3) was extracted, and the organic phase was washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by reverse phase column (FA) (ACN:H20 = 30%, 50%) to obtain compound 6-2 (1.44 g, 10.6%). 1 H NMR (400 MHz, DMSO-d6) δ 7.94-7.69 (m, 2H), 4.17-4.04 (m, 2H), 1.97-1.84 (m, 6H), 1.12 (dd, J = 14.7, 7.6 Hz, 3H). LCMS (ESI, m / z): 184 [M+H] + .

[0235] Second step: To a solution of compound 6-2 (1 g, 5.72 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M, 4.6 ml, 11.43 mmol) slowly at -78 °C. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 x 3 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: tetrahydrofuran = 5: 1) to give compound 6-3 (456 mg, yield 46.9%). LCMS (ESI, m / z): 179.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 4.33 (s, 2H), 1.95 (s, 6H).

[0236] Third step: To a solution of compound 6-3 (245 mg, 1.375 mmol) in ethanol (4 mL) was added hydrochloric acid (12 M, 0.34 mL, 4.125 mmol) and cyclopropylhydrazine hydrochloride (448 mg, 4.125 mmol). The reaction was stirred at 70 °C overnight. The reaction was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 x 3 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1: 1) to give compound 6-4 (189 mg, yield 59.2%). LCMS (ESI, m / z): 233.2 [M+H] + .

[0237] Fourth step: A reaction flask was charged with compound 6-4 (0.40 g, 1.0 eq), 1,3-dicyclohexylcarbodiimide (0.53 g, 1.5 eq) and dichloromethane (10 mL), followed by the addition of HCOOH (0.20 g, 2.0 eq). The reaction was stirred at room temperature for 12 hours. The reaction was monitored by thin layer chromatography. The reaction was diluted with dichloromethane (20 mL) and washed with saturated Na2CO3 aqueous solution (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give compound 6-5 (0.36 g, yield: 80%).

[0238] Fifth step: Take a reaction flask, add 2-chloro-4-(methylthio)-5- (trifluoromethyl)pyrimidine (0.30 g, 1.0 eq), compound 6-5 (0.34 g, 1.0 eq), dimethyl sulfoxide (5 mL) and Cs2CO3(0.86 g, 2.0 eq) in sequence, place the reaction flask into a 50 °C oil bath and stir for 2 min, then heat to 90 °C and stir for 2 h. Monitor the reaction completion by LCMS, cool to room temperature, extract with ethyl acetate 20 mL*2, wash with saturated NaCl solution, dry over anhydrous Na2SO4, filter, concentrate to give compound 6-6 (0.48 g, yield: 74.8%). LCMS (ESI, m / z): 425.05 [M+H] + .

[0239] Sixth step: Take a reaction flask, add compound 6-6 (0.26 g, 1.0 eq) and dissolve in dimethyl sulfoxide (5 mL), stir at 0 °C for 5 min, then add meta-chloroperoxybenzoic acid (0.19 g, 1.5 eq), and stir at room temperature for 12 h. TLC detection shows that the starting material has been completely reacted, directly add silica gel to the sample, and purify the crude product by normal phase flash to give compound 6-7 (0.21 g, yield: 78.0%). LCMS (ESI, m / z): 462.94 [M+Na] + .

[0240] Seventh step: Take a reaction flask, add compound 6-7 (20 mg, 1.0 eq), 2- aminoethyl dimethyl phosphine oxide (9 mg, 1.0 eq), and tetrahydrofuran (2 mL) in sequence, stir at room temperature, then add triethylamine (30 mg, 5.0 eq), and stir at room temperature for 2 h. TLC detection shows that the starting material has been completely reacted, and purify by preparative thin layer chromatography to give compound 6. 1 HNMR (400 MHz, CD3OD) δ: 9.25 (s, 1H), 8.12 (s, 1H), 7.71 (s, 2H), 7.29 (m, 1H), 5.79 (s, 1H), 3.60-3.44 (m, 2H), 3.41-3.33 (m, 1H), 1.91 (s, 6H), 1.88-1.80 (m, 2H), 1.34-1.30 (d, J = 16 Hz, 6H), 0.85-0.82 (m, 4H). LCMS (ESI, m / z): 498.08 [M+H] + .

[0241] Example 7-8:

[0242] Refer to Examples 2, 6, synthesize Examples 7, 8.

[0243] Example 9: Synthesis of 2-(l-cyclopropyl-5-((4-(ethylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-lH-pyrazol-3-yl)-2-methylthiophene 1,1- dioxide (Compound 9)

[0244] First step: In a reaction flask, add compound 9-1 (5 g, 41.67 mmol) and tetrahydrofuran (50 mL), protect with argon, add LiHMDS (20.8 mL, 41.67 mmol, 2 mol / L) solution of tetrahydrofuran at -78 °C, add benzyl chloroformate (7.08 g, 41.67 mmol) after stirring for 1 h, and stir at -78 °C for 1 h. After the reaction is completed, quench with water (150 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:10)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound 9-2 (5 g, yield: 47.26%). LCMS (ESI, m / z): 272.2 [M+18] + ; 1 HNMR (400 MHz, DMSO-d6) δ: 7.40-7.34 (m, 5H), 5.22 (s, 2H), 4.28 (t, J = 8.4 Hz, 1H), 3.30-3.24 (m, 1H), 3.18-3.10 (m, 1H), 3.00-2.98 (m, 1H), 2.36-2.31 (m, 1H), 2.19-2.05 (m, 2H).

[0245] Second step: In a reaction flask, add compound 9-2 (1 g, 3.94 mmol), Cs2CO3 (2.57 g, 7.88 mmol), and N,N-dimethylformamide (15 mL), and finally add CH3I (1.12 g, 7.88 mmol), and stir at room temperature overnight. After the reaction is completed, dilute with water (60 mL), extract with ethyl acetate (20 mL) three times, combine the organic phases, and backwash three times with saturated brine. Dry the organic phase, evaporate the solvent under reduced pressure to obtain a crude product, purify the crude product by silica gel column chromatography [eluent: petroleum ether-tetrahydrofuran (100:0-100:30)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound 9-3 (1 g, yield: 95%). LCMS (ESI, m / z): 286.3 [M+18] + ; 1HNMR (400 MHz, DMSO-d6) δ: 7.40-7.34 (m, 5H), 5.23-5.15 (m, 2H), 3.27-3.22 (m, 2H), 2.72-2.69 (m, 1H), 2.10-1.99 (m, 3H), 1.52 (s, 3H).

[0246] Step 3: In a reaction flask, acetonitrile (245 mg, 5.97 mmol) and super dry tetrahydrofuran (10 mL) were added, after argon protection, n-BuLi (5.38 mL, 5.39 mmol, 1 mol / L) was added dropwise at -78°C, stirred for 1 hour, then compound 9-3 (800 mg, 2.98 mmol) was added, stirred for 2 hours. The reaction was complete, quenched with water (30 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by silica gel column [eluent: dichloromethane-methanol (100:0-100:10)], the eluate was collected, and the solvent was removed under reduced pressure to obtain compound 9-4 (420 mg, yield: 70%). LCMS (ESI, m / z): 219.2 [M+18] + .

[0247] Step 4: In a reaction flask, compound 9-4 (300 mg, 1.49 mmol) and ethanol (10 mL) were added, then cyclopropylhydrazine hydrochloride (488 mg, 4.48 mmol) was added, stirred at 90°C overnight, the reaction was complete, the reaction liquid was adjusted to pH about 8 with sodium bicarbonate aqueous solution, extracted with water and ethyl acetate, the organic phase was dried and then mixed with silica gel, purified by silica gel column [eluent: dichloromethane-methanol (100:0-100:5)], the eluate was collected, and the solvent was removed under reduced pressure to obtain compound 9-5 (330 mg, yield: 86%). LCMS (ESI, m / z): 256.3 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ: 5.29 (s, 1H), 5.26 (s, 2H), 3.19-3.12 (m, 2H), 3.06-3.02 (m, 1H), 2.63-2.59 (m, 1H), 2.17-1.92 (m, 3H), 1.48 (s, 3H), 0.91-0.89 (m, 4H).

[0248] Step 5: In a reaction flask, add 007-3 (100 mg, 0.39 mmol) and dioxane (10 mL), then add compound 9-5 (88 mg, 0.39 mmol), p-toluenesulfonic acid (34 mg, 0.19 mmol), stir at 90 °C overnight. After the reaction is completed, the solvent is removed under reduced pressure to obtain a crude product, which is purified by silica gel column [eluent: dichloromethane-methanol (100:0-100:8)], the eluent is collected, and the solvent is removed under reduced pressure to obtain a crude product. The crude product is purified by C18 reverse phase column, the eluent is collected, the solvent is removed under reduced pressure, freeze-dried to obtain compound 9. LCMS (ESI, m / z): 445.0 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ: 9.46 (br, 1H), 8.18 (s, 1H), 7.21 (br, 1H), 6.40 (s, 1H), 3.54-3.48 (m, 1H), 3.44-3.38 (m, 2H), 3.23-3.18 (m, 1H), 3.12-3.04 (m, 1H), 2.69-2.64 (m, 1H), 2.20-2.02 (m, 3H), 1.56 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.97-0.92 (m, 4H).

[0249] Example 10: Synthesis of N2-(3-(1-(2H-1,2,3-triazol-2-yl)cyclopropyl)-1- cyclopropyl-1H-pyrazol-5-yl)-N4-isopropyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 10)

[0250] Step 1: Take a reaction flask, first add compound 10-1 (40.0 g, 1.0 eq), N,N- dimethylformamide (250 mL) and methyl 2,4-dibromobutyrate (150.0 g, 1.0 eq), replace with nitrogen ball for 3 times, add CS2CO3 (376.1 g, 2.0 eq) in batches under ice water bath, react overnight. Monitor the reaction completion by LCMS, add 2 L water to the reaction solution, then separate, extract the aqueous phase with ethyl acetate (3*1 L), wash the combined organic phase with saturated NaCl solution (3*500 mL), dry, filter and rotary evaporate to obtain compound 10-2 (54 g, yield: 56%). LC-MS (ESI, m / z): 167.87 [M+H] + .

[0251] Second step: Take the reaction bottle, add compound 10-2 (50 g, 1.0 eq), MeCN (25.8 g, 2.1 eq) and tetrahydrofuran (100 mL) in turn, then add t-BuOK / tetrahydrofuran solution (1 mol / L) (600 mL, 2.0 eq) under ice bath, and react overnight. Monitor the reaction completion by LCMS, add 50 mL water to the reaction system, extract once with 100 mL ethyl acetate, separate the aqueous phase, adjust the pH to 1-2 with HCl, add ethyl acetate for extraction, wash the organic phase with saturated NaCl solution (3*50 mL), dry, filter and rotary evaporate to obtain compound 10-3 (32 g, yield: 58%). LC-MS (ESI, m / z): 176.88 [M+H] + .

[0252] Third step: Take the sealed tube, add compound 10-3 (10.0 g, 1.0 eq), cyclopropyl hydrazine hydrochloride (7.4 g, 2.0 eq), ethanol (100 mL) and 6M HCl (28 mL) in turn, and react at 60°C overnight. Monitor the reaction completion by LCMS, add 50 mL water to the reaction liquid, then separate, extract the aqueous phase with ethyl acetate (3*15 mL), combine the organic phases, wash with saturated NaCl solution (3*20 mL), dry, filter and rotary evaporate to obtain compound 10-4 (4.45 g, yield: 34%). LC-MS (ESI, m / z): 230.91 [M+H] + .

[0253] Fourth step: Take the reaction bottle, add compound 10-4 (2.3 g, 1.0 eq) and 2,4-dichloro-5-trifluoromethyl pyrimidine (2.4 g, 5 mL) in turn, dissolve in 40 mL tert-butanol, then add N,N-diisopropyl ethylamine (3.9 g, 2.0 eq), continue to stir at room temperature for 3 hours. Monitor the reaction completion by LCMS, sample the reaction liquid and pass through the column, concentrate to obtain compound 10-5 (1.0 g, yield: 24%). LC-MS (ESI, m / z): 410.83 [M+H] + .

[0254] Fifth step: Take the sealed tube, add compound 10-5 (30 mg, 1.0 eq) and isopropylamine (30 mg, 5.0 eq) in turn, dissolve in 3 mL 1,4-dioxane, then add N,N-diisopropyl ethylamine (94 mg, 10 eq), and react at 60°C overnight. Monitor the reaction completion by LCMS, directly prepare high performance liquid chromatography, and freeze-dry to obtain compound 10. 1HNMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 8.12 (s, 1H), 7.80 (s, 2H), 7.36 (d, J = 8.0 Hz, 1H), 5.71 (s, 1H), 4.10 (s, 1H), 3.43-3.41 (m, 1H), 1.61-1.51 (m, 4H), 1.08-1.06 (d, J = 6.4 Hz, 6H), 0.92-0.87 (m, 4H). LC-MS (ESI, m / z): 433.91 [M+H] + .

[0255] Examples 11-26

[0256] Examples 11-26 were synthesized according to the procedures described in Reference Examples 2, 10.

[0257] Example 27: Synthesis of N4-methyl-N2-(3-methyl-1-(5,5,5-trifluoro-2-methylpent-3-yn-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 27)

[0258] First Step: In a reaction flask, add compound 27-1 (5 g, 39.3 mmol), ethyl 2-bromo-2-methylpropanoate (11.51 g, 59.0 mmol), potassium carbonate (8.16 g, 59.0 mmol) and N,N-dimethylformamide (50 mL), stir at room temperature overnight. After the reaction is completed, dilute with water (250 mL), extract with ethyl acetate (50 mL x 3), combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain a crude product, purify it by silica gel column [eluent: petroleum ether-ethyl acetate (100:0-80:20)], collect the eluate, evaporate the solvent under reduced pressure to obtain compound 27-2 (9.2 g, yield: 96.9%). LC-MS (ESI, m / z): 242.1 [M+H] + .

[0259] Second step: In a reaction flask, add compound 27-2 (9.0 g, 37.3 mmol) and methanol (100 mL), cool the reaction flask to 0 °C in an ice bath, and add sodium borohydride (2.82 g, 74.6 mmol) portionwise below 5 °C. Stir at 0 °C for 2 hours. After the reaction is complete, evaporate the methanol under reduced pressure, dissolve the residue in ethyl acetate (50 mL), wash the organic phase with water (50 mL) and saturated brine (50 mL) separately, dry over anhydrous sodium sulfate, filter, and concentrate the organic phase under reduced pressure to obtain compound 27-3 (7.0 g, yield: 94.2%). LC-MS (ESI, m / z): 200.2 [M+H] + .

[0260] Third step: In a reaction flask, add compound 27-3 (6.8 g, 34.1 mmol) and dichloromethane (100 mL), and add Dess-Martin oxidant (28.96 g, 68.3 mmol) in an ice bath. Stir at room temperature overnight. After the reaction is complete, quench the reaction by adding a sodium thiosulfate solution (50 mL), wash the organic phase with a sodium bicarbonate solution and saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a crude product, which is purified by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-80:20)] to obtain compound 27-4 (4.9 g, yield: 72.8%). LC-MS (ESI, m / z): 198.1 [M+H] + .

[0261] Fourth step: In a reaction flask, add compound 27-4 (4.9 g, 24.8 mmol), potassium carbonate (6.87 g, 49.7 mmol), and methanol (50 mL), and slowly add dimethyl (1-diazo-2-oxopropyl)phosphonate (7.16 g, 37.3 mmol) to the reaction solution. Stir at room temperature overnight. After the reaction is complete, directly purify the reaction solution by silica gel column chromatography [eluent: petroleum ether-ethyl acetate (100:0-90:10)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound 27-5 (3.8 g, yield: 79.2%). LC-MS (ESI, m / z): 194.1 [M+H] + .

[0262] Fifth step: In a reaction flask, add potassium carbonate (439 mg, 3.18 mmol), copper iodide (303 mg, 1.59 mmol), TMEDA (185 mg, 1.59 mmol) and dry N,N-dimethylformamide (5 mL), and stir the mixture at room temperature for 20 minutes. Add TMSCF3 (301 mg, 2.12 mmol) to the reaction mixture, and stir at room temperature for 20 minutes. Cool the reaction mixture to 0 °C with an ice bath, and dissolve TMSCF3 (301 mg, 2.12 mmol) and compound 27-5 (301 mg, 2.12 mmol) in N,N-dimethylformamide (5 mL). Slowly add the solution to the reaction mixture, and then slowly warm to room temperature. Stir at room temperature overnight. After the reaction is complete, dilute the mixture with water (30 mL), extract with ethyl acetate (20 mL x 3), wash the combined organic phases with saturated brine twice, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain a crude product. Purify the crude product by column chromatography on silica gel [eluent: petroleum ether-ethyl acetate (100:0-80:20)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound 27-6 (120 mg, yield: 43.4%). LC-MS (ESI, m / z): 262.2 [M+H] + .

[0263] Sixth step: In a reaction flask, add compound 27-6 (123 mg, 0.47 mmol), NH4Cl (126 mg, 2.36 mmol), EtOH (6 mL), and water (3 mL), and add iron powder (132 mg, 2.36 mmol) with vigorous stirring. Heat the mixture to 80 °C under argon protection, and stir for 2 hours. After the reaction is complete, filter the mixture, extract the filtrate with ethyl acetate three times, dry the combined organic phases, and evaporate the solvent under reduced pressure to obtain a crude product. Purify the crude product by column chromatography on silica gel [eluent: petroleum ether-ethyl acetate (100:0-100:50)], collect the eluate, and evaporate the solvent under reduced pressure to obtain compound 27-7 (67 mg, yield: 61.7%). LC-MS (ESI, m / z): 232.1 [M+H] + .

[0264] Seventh step: In a reaction flask, add compound 27-7 (30 mg, 0.13 mmol) and dioxane (5 mL), and then add intermediate INT3 (27 mg, 0.13 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol). Stir the mixture at 90 °C overnight. After the reaction is complete, dilute the mixture with ethyl acetate, wash the organic phase with saturated sodium bicarbonate, dry, and evaporate the solvent under reduced pressure to obtain a crude product. Purify the crude product by C18 reverse-phase column chromatography, collect the eluate, evaporate the solvent under reduced pressure, and lyophilize to obtain compound 27. LC-MS (ESI, m / z): 407.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (br s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.00 (s, 1H), 2.84-2.79 (m, 3H), 2.18 (s, 3H), 1.95 (s, 6H).

[0265] Examples 28-29

[0266] Reference Example 27, Examples 28-29 were synthesized.

[0267] Example 30: Synthesis of N2-(1-cyclopropyl-3-(2-(5-(ethylthio)-2H-tetrazol-2-yl)prop-2-yl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 30)

[0268] First step: Take a reaction flask, add 5-ethylthiotetrazole (1.302 g, 1.0 eq) and N,N-dimethylformamide (20 mL), TEA (2.024 g, 2.0 eq), then slowly drop in Compound 30-1 (3.621 g, 2.0 eq) and KI (0.166 g, 0.1 eq), then react at 60 °C overnight. After the reaction is complete by LCMS detection, add 100 mL of water to the reaction solution, then separate the liquid, extract the aqueous phase with EA (3*50 mL), wash the organic phase with saturated NaCl solution (3*30 mL), dry, filter and rotary evaporate, then purify the crude product by normal phase column chromatography to obtain Compound 30-2 (1.3 g, yield: 56%). LC-MS (ESI, m / z): 230.95 [M+H] + .

[0269] Second step: Take a three-necked flask, add Compound 30-2 (1.200 g, 1.0 eq), super dry acetonitrile (0.450 g, 2.1 eq) and tetrahydrofuran (20 mL) in turn, then stir for ten minutes in an ice bath under nitrogen atmosphere, then add 1N potassium tert-butoxide tetrahydrofuran solution (10.5 mL, 2.0 eq), after adding, let it naturally warm to room temperature and react, then let it react overnight. After the reaction is complete by LCMS detection, directly add the reaction solution to water (50 ml), then extract with ethyl acetate (50 ml), separate the aqueous phase, then adjust the pH to about 3 using 6N hydrochloric acid aqueous solution, then extract with ethyl acetate (50 ml), separate the organic phase, then dry and concentrate to obtain Compound 30-3 (1.2 g, yield: 96%). LC-MS (ESI, m / z): 239.96 [M+H] + .

[0270] Third Step: Take a vial, add compound 30-3 (0.100 g, 1.0 eq), cyclopropylhydrazine (0.114 g, 1.05 eq), 6N aqueous hydrochloric acid (0.2 mL, 3.0 eq) and ethanol (4 mL) successively, and react at 60 °C overnight. Monitor the completion of the reaction by LCMS. Dilute the reaction mixture with ethanol, dry over anhydrous sodium sulfate, and then directly filter and concentrate to obtain compound 30-4 (0.080 g, yield: 63%). LC-MS (ESI, m / z): 164.02.

[0271] Fourth Step: Take a vial, add compound 30-4 (0.080 g, 1.0 eq), intermediate INT2 (0.061 g, 1.0 eq), Pd(OAc)2 (0.012 g, 0.2 eq), Xantphos (0.063 g, 0.4 eq), Cs2CO3 (0.266 g, 3.0 eq) and dioxane (5 mL) successively, replace with nitrogen for three times, and react at 100 °C for 5 hours. Monitor the completion of the reaction by LCMS. Wash the reaction mixture with water, extract with ethyl acetate, dry and concentrate the organic phase, and then send for preparation. Lyophilize to obtain compound 30. LC-MS (ESI, m / z): 483.13 [M+H] + . 1 HNMR (400 MHz, CD3OD) δ: 8.10 (s, 1H), 6.22 (s, 1H), 3.44-3.38 (m, 2H), 3.37-3.33 (m, 1H), 3.15 (dd, J = 12.0 Hz, 8.0 Hz, 2H), 2.09 (s, 6H), 1.35 (t, J = 4.0 Hz, 3H), 1.12 (t, J = 8.0 Hz, 3H), 1.08-0.99 (m, 4H).

[0272] Example 31: Synthesis of N2-(1-cyclopropyl-3-(2-(thiazol-4-yl)prop-2-yl)-1H- pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 31)

[0273] First Step: To a solution of compound 31-1 (505 mg, 3.53 mmol) in ethanol (20.5 mL) was added dichlorosulfoxide (833 mg, 7.00 mmol) dropwise. After the addition was completed, it was stirred at room temperature overnight. After the completion of the reaction was monitored by LCMS, the solvent was removed by distillation under reduced pressure. Ethyl acetate was added for dilution, and the mixture was washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain compound 31-2 (540 mg, yield: 89.4%). LC-MS (ESI, m / z): 172.2 [M+H] + .

[0274] Second Step: To a solution of compound 31-2 (270 mg, 1.58 mmol) in N,N- dimethylformamide (5.3 mL) was added NaH (60% w / w, 192 mg, 4.80 mmol) portion wise at 0 °C, stirred for 5 min at 0 °C, then Mel (897 mg, 6.32 mmol) was added, after the addition was completed, the reaction mixture was stirred at room temperature overnight. Upon completion of the reaction as monitored by LCMS, the reaction was quenched with ice cold water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography [eluent: petroleum ether- ethyl acetate (100:0-100:17)] to afford compound 31-3 (140 mg, yield: 44.6%). LC-MS (ESI, m / z): 200.2 [M+H] + .

[0275] Third Step: To a solution of acetonitrile (50 mg, 0.60 mmol) in tetrahydrofuran (13.0 mL) was added n-butyllithium (2.5 M, 0.4 mL, 1.22 mmol) at -78 °C, stirred for 5 min, then compound 31-3 (119 mg, 0.60 mmol) was added, after the addition was completed, the reaction mixture was stirred at -78 °C for 3 h. Upon completion of the reaction as monitored by LCMS, the reaction was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography [eluent: petroleum ether- tetrahydrofuran (100:0-100:25)] to afford compound 31-4 (120 mg, yield: >99.9%). LC-MS (ESI, m / z): 195.2 [M+H] + .

[0276] Fourth Step: To a solution of compound 31-4 (39 mg, 0.20 mmol) in isopropanol (4.5 mL) was added cyclopropylhydrazine hydrochloride (26 mg, 0.24 mmol), then the reaction mixture was stirred at 80 °C for 6 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was directly concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography [eluent: petroleum ether- tetrahydrofuran (100:0-100:75)] to afford compound 31-5 (20 mg, yield: 40.1%). LC-MS (ESI, m / z): 249.2 [M+H] + .

[0277] Step 5: To a solution of compound 31-5 (10 mg, 0.040 mmol) in 1,4-dioxane (3.0 mL) was added intermediate INT2 (11 mg, 0.049 mmol) and p-toluenesulfonic acid (8 mg, 0.46 mmol) and then warmed to 90 °C with stirring overnight. When the reaction was complete as monitored by LCMS, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography and preparative high-performance liquid chromatography to give compound 31. LC-MS (ESI, m / z): 438.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ: 9.27 (br, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.18-7.05 (m, 1H), 6.07 (s, 1H), 3.50-3.38 (m, 1H), 3.31-3.18 (m, 2H), 1.62 (s, 6H), 1.02 (t, J = 6.8 Hz, 3H), 0.98-0.91 (m, 2H), 0.90-0.80 (m, 2H).

[0278] Examples 32-34

[0279] Examples 32-34 were synthesized according to the procedures described in Reference Examples 30, 31.

[0280] Example 35: Synthesis of N2-(3-(2-(2H-1,2,3-triazol-2-yl)prop-2-yl)-1-(oxetan-3-yl)-1H- pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Compound 35)

[0281] Step 1: Take a vial, add compound 6-3 (0.521 g, 1.0 eq), hydrazine hydrate (0.264 g, 1.5 eq), 6N aqueous hydrochloric acid (1.3 mL, 3.0 eq) and ethanol (10 mL) successively, and react at 60 °C overnight. When the reaction was complete as monitored by LCMS, the reaction was diluted with ethanol and dried over anhydrous sodium sulfate, then directly filtered and concentrated to give crude compound 35-2 (1.102 g, yield: 100%). LC-MS (ESI, m / z): 193.05 [M+H] + .

[0282] Second step: Take the sealed tube, add compound 35-2 (0.948 g, 1.0 eq), N, N- dimethylformamide-DMA (2.350 g, 4.0 eq) and dioxane (15 mL) in turn, and react at 100°C for 2 hours. Monitor the reaction completion by LCMS, and directly dry sample on column to purify to obtain white solid compound 35-3 (420 mg, yield: 35%). LC-MS (ESI, m / z): 248.09 [M+H] + .

[0283] Third step: Take the reaction bottle, add compound 35-3 (0.216 g, 1.0 eq) and N, N- dimethylformamide (4 ml) in turn, then stir for ten minutes under nitrogen atmosphere and ice bath condition, add sodium hydride (0.081 g, 2.0 eq), continue to stir for 15 minutes, then add 3- iodooxetane (0.241 g, 1.5 eq), first stir for ten minutes to restore to room temperature, then stir for 5 hours at 60°C. Monitor the reaction completion by LCMS, pour the reaction liquid into water (50 ml), then extract with ethyl acetate (50 ml), dry and concentrate the organic phase, then separate by preparative thin layer chromatography to obtain compound 35-4 (102 mg, yield: 38.4%). LC-MS (ESI, m / z): 304.01 [M+H] + .

[0284] Fourth step: Take the sealed tube, add compound 35-4 (0.102 g, 1.0 eq), sodium hydroxide aqueous solution (4 M, 5 ml) and methanol (5 ml) in turn, then react at 80°C for 2 hours, then add sodium hydroxide (0.800 g), continue to react at 80°C for 3 hours. Monitor the reaction completion by LCMS, then separate by preparative thin layer chromatography to obtain compound 35-5 (51 mg, yield: 61%). LC-MS (ESI, m / z): 249.02 [M+H] + .

[0285] Fifth step: Take the reaction bottle, add compound 35-5 (0.030 g, 1.0 eq), intermediate INT2 (0.033 g, 1.0 eq), Pd2(dba)3 (0.022 g, 0.2 eq), 1, 1'-binaphthalene-2, 2'- bisdiphenylphosphine (0.022 g, 0.2 eq), sodium tert-butoxide (0.024 g, 2.0 eq) and dioxane (3 ml) in turn, then replace with nitrogen for three times, react at 100°C for 5 hours. Monitor the reaction completion by LCMS, then wash the reaction liquid with water, extract with ethyl acetate, dry and concentrate the organic phase, then separate by preparative high performance liquid chromatography to obtain compound 35. LC-MS (ESI, m / z): 438.10 [M+H] + .1 HNMR (400 MHz, CDC13) δ: 8.11 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.62 (s, 2H), 6.01 (s, 1H), 5.49 (p, J = 6.8 Hz, 1H), 5.35 (s, 1H), 5.24-5.20 (m, 2H), 4.95 (dd, J = 8.0, 6.8 Hz, 2H), 3.40-3.33 (m, 2H), 2.13 (s, 6H), 1.19 (t, J = 7.2 Hz, 3H).

[0286] Examples 36-37

[0287] Referring to Example 35, Examples 36-37 were synthesized.

[0288] Biological Evaluation

[0289] Test Example 1: LRRK2 Kinase Inhibitory Activity Assay

[0290] Purpose of the Experiment

[0291] The time-resolved fluorescence resonance energy transfer (TR-FRET) technique was used to detect the energy transfer (520nM / 485nM fluorescence signal ratio) that occurs upon binding of the phosphorylated group of Fluorescein-ERM (LRRKtide) peptide to Tb-Fluorescein RM (pLRRKtide) Antibody. The IC 50 values of the test compounds against LRRK2 kinase were calculated.

[0292] Principle of the Experiment

[0293] This protocol describes an in vitro method for measuring the phosphorylation of a peptide substrate by WT-LRRK2 enzyme. The kinase reaction is performed by incubating a fluorescein-labeled substrate with recombinant human kinase and ATP. The kinase activity is determined using the Lantha Screen TM Kinase Activity Assay. The kinase activity is determined using the Lantha Screen TM In the kinase reaction, a terbium-labeled antibody (for detection of the phosphorylated product) binds to the phosphorylated fluorescein-labeled substrate, resulting in an increase in the TR-FRET value. The TR-FRET value is determined by the ratio of the FRET-specific signal measured at 520 nm filter to the signal measured at 495 nm filter. The amount of antibody bound to the tracer is directly proportional to the amount of phosphorylated substrate present. Thus, the kinase activity can be measured by the increase in the TR-FRET value.

[0294] Materials:

[0295] Reagents:

[0296] Consumables:

[0297] Instrument:

[0298] Experimental procedure:

[0299] 1. Add dimethyl sulfoxide solution of test compound to 384-well plate by Echo 655 non-contact nanoscale ultrasonic liquid handling system; highest concentration 10 uM, 3-fold gradient dilution, 11 concentration gradients.

[0300] 2. Prepare enzyme and polypeptide mixed solution (final concentration: 2 nM enzyme + 0.4 uM Fluorescein-ERM (LRRKtide) peptide) with freshly prepared reaction solution, add 5 uL to the 384-well plate with the existing compound, centrifuge at 1000 rpm / min for 1 min. Incubate at room temperature for 15 min;

[0301] 3. Add 5 uL ATP (final concentration: 38 uM), centrifuge at 1000 rpm / min for 1 min. React at room temperature for 120 min;

[0302] 4. Add 10 uL detection reagent: Tb-Fluorescein RM (pLRRKtide) Antibody (final concentration: 0.25 nM) and EDTA (final concentration: 10 mM), centrifuge at 1000 rpm / min for 1 min. React at room temperature for 30 min;

[0303] 5. Envison detects TR-TRET fluorescence signal, mirror 447 (D400 / D505), filter 275 (520 nm) and 102 (485 nm);

[0304] 6. Calculate the inhibition of enzyme activity of the compound by signal ratio (520 nm / 485 nm), and calculate IC 50 value by software XLfit 5 curve fitting.

[0305] Experimental results:

[0306] The calculation results of the inhibitory activity of some example compounds on LRRK2 are shown in the following table.

[0307] Table 1

[0308] Test Example 2: In vitro microsomal stability experiment

[0309] Materials:

[0310] Liver microsomes: Human and animal microsomes were purchased from Corning or Xenotech and stored at -80 °C.

[0311] Reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: BONTAC, article number: BT04

[0312] Control compounds: Testosterone, Diclofenac, Propafenone

[0313] Experimental procedure:

[0314] 1. Preparation of working solutions

[0315] Stock solution: 10 mM solution of dimethyl sulfoxide

[0316] Working concentration preparation: 100% acetonitrile diluted to 100 mM (organic phase content: 99% ACN, 1% dimethyl sulfoxide)

[0317] 2. Experimental procedure

[0318] Prepare 2 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate, respectively.

[0319] Add 445 pL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) to the T60 incubation plate and NCF60 incubation plate, respectively, and then place the above incubation plates in a 37 °C water bath for pre-incubation for about 10 minutes.

[0320] After pre-incubation, add 5 pL of test sample or control compound working solution to the T60 incubation plate and NCF60 incubation plate, respectively, and mix well. Add 50 pL of potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction.

[0321] Add 180 pL of termination solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 uL of NADPH regeneration system working solution to the T0 termination plate, and take 54 pL of sample from the T60 incubation plate to the T0 termination plate (T0 sample production). In the Blank plate, only add 54 pL of microsomal working solution, 6 uL of NADPH regeneration system working solution and 180 pL of termination solution.

[0322] Add 44 μL of NADPH Regeneration System Working Solution to each well of the T60 Incubation Plate to start the reaction. Thus, the final concentrations of the compound, testosterone, diclofenac and propafenone in the sample of test article or control compound, the concentration of liver microsomes, and the final concentrations of dimethyl sulfoxide and acetonitrile in the reaction system are 1 μM, 0.5 mg / mL, 0.01% (v / v) and 0.99% (v / v), respectively.

[0323] After incubation for an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes), add 180 μL of Stop Solution (a solution of 250 nM tolbutamide and 250 nM labetalol in acetonitrile) to each sample well of the Stop Plate, and then remove 60 μL of sample from the T60 Incubation Plate or NCF60 Incubation Plate to stop the reaction.

[0324] Centrifuge all sample plates at 3220 x g for 20 minutes, and then dilute 80 μL of supernatant from each well into 240 μL of purified water for liquid chromatography tandem mass spectrometry analysis.

[0325] Liquid chromatography tandem mass spectrometry analysis: All samples are analyzed by injection.

[0326] 1. Sample Analysis

[0327] In this study, the sample analysis of test article and control compounds, testosterone, diclofenac and propafenone, is determined by liquid chromatography tandem mass spectrometry (LC-MS / MS) method.

[0328] 2. Data Analysis

[0329] The in vitro elimination rate constant k of test article and control compounds is obtained by converting the ratio of peak area of compound to internal standard in the following formula into the percentage of remaining e :

[0330] When

[0331] The in vitro liver microsomal intrinsic clearance (CLint(mic)) and liver intrinsic clearance (CLint(liver)) are calculated from ke

[0332] CLint(mic) = 0.693 / T1 / 2 / microsomal protein content (mg / mL of microsomal concentration during incubation)

[0333] CLint(liver) = CLint(mic) x microsomal protein content in liver (mg / g) x liver weight / body weight ratio

[0334] The parameters used in the formula are shown in the following table.

[0335] The in vitro microsomal stability results of some example compounds in human (HLM) and rat (RLM) are shown in the following table.

[0336] Table 2

[0337] Test Example 3: Compound pharmacokinetic evaluation

[0338] Control drug 1 Refer to the synthesis of compound 78 on page 73 of the specification of WO2017218843A1.

[0339] Test Example 3-1:

[0340] Experimental materials

[0341] SD rats (male, 6 weeks old, body weight 180-210 g).

[0342] Experimental operation

[0343] The rodent pharmacokinetic characteristics of the compound after oral administration were tested according to the standard protocol. In the experiment, the candidate compound was prepared into a 1 mg / mL clear solution, and a single oral administration was given to the rats. The oral solvent was 60% polyethylene glycol 400 / 40% aqueous solution. Male SD rats were used in this project, and oral gavage was given, and the dose was 5 mg / kg. The plasma was collected at 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. First, 10 μL of the plasma sample was removed into a 96-well plate, 800 μL of acetonitrile solution containing an internal standard was added to precipitate the protein, and 800 rpm vortex mixing was performed for 10 minutes, followed by centrifugation at 3220 g, 4°C for 15 minutes; secondly, 50 μL of supernatant was transferred to another clean 96-well plate, and centrifuged at 3220 g, 4°C for 5 minutes; finally, the blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and the pharmacokinetic parameters such as peak concentration (C max ), half-life (T 1 / 2 ), peak time (T max ), area under the curve (AUC 0-last ) were calculated.

[0344] The results of some example compounds are shown in the following table.

[0345] Table 3-1

[0346] Test Example 3-2:

[0347] Experimental materials

[0348] C57BL / 6J mice (male, 7 weeks old, body weight 20.0-24.0 g)

[0349] Experimental procedure

[0350] The pharmacokinetic profiles of the compounds in rodents after oral administration were tested according to standard protocols. The candidate compounds were formulated into 1 mg / mL clear solutions and administered to mice as a single oral dose. The vehicle was 10% dimethylsulfoxide / 10% Tween 80 / 20% petroleum ether G400 in water. Male C57BL / 6J mice were used in this project and administered orally by gavage at a dose of 10 mg / kg. Plasma was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. First, 5 μL of plasma sample was removed into a 96-well plate, and 200 μL of acetonitrile containing an internal standard was added to precipitate the protein. After vortex mixing for 5 minutes at 1000 rpm, the mixture was centrifuged at 3220 g at 4°C for 10 minutes. The supernatant was then analyzed quantitatively for drug concentration by LC-MS / MS analysis, and pharmacokinetic parameters such as clearance (Cl), peak concentration (Cmax), half-life (T1 / 2), time to peak (Tmax), and area under the curve (AUC0-last) were calculated.

[0351] The results for some of the compounds of the examples are shown in the following tables.

[0352] Table 3-2

[0353] Test Example 4: Pharmacokinetic evaluation of compounds: brain tissue to plasma drug concentration ratio

[0354] Experimental materials

[0355] SD rats (male, 6 weeks old, body weight 180-210 g).

[0356] Experimental procedure

[0357] The pharmacokinetic profile of the compounds in rodents after oral administration was tested using a standard protocol. In the experiment, the candidate compounds were formulated into a 1 mg / mL clear solution and administered to rats as a single oral dose. The oral vehicle was 20% HP-beta-CD in water. Male SD rats were used in this project and administered orally by gavage at a dose of 5 mg / kg. At 0.5, 2, and 4 hours after administration, whole brains were collected. The tissue samples were homogenized with 5-fold homogenization buffer. Finally, the sample concentrations were quantitatively analyzed using LC-MS / MS analysis method, and the brain tissue and plasma drug concentration ratios (B / P) and the concentration ratios of unbound drug in brain tissue to unbound drug in plasma (Kp,uu) were calculated. Kp,uu is a key parameter for evaluating the distribution equilibrium of a compound between blood and brain, which reflects the effects of passive diffusion and transporters: when Kp,uu is close to 1, it is a relatively ideal compound property, which has good permeability and is a non-transporter substrate; when Kp,uu is much less than 1, it indicates that the compound can be a transporter substrate or has poor permeability; when Kp,uu is greater than 1, it is possible that active transporters are involved in the transmembrane transport process of the compound.

[0358] The results of some of the example compounds are shown in the following table.

[0359] Table 4

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: A is a five-membered heteroaryl group containing 2 or 3 N atoms; X is N or CH; Y is selected from single bond, O, S, NH or NRy, and Ry is C. 1-6 alkyl; R 1 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or 5-6 membered heteroaryl groups are optionally replaced by halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-6 Haloalkyl, C 1-3 Alkoxy or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group; R 2 Selected from C 1-6 Alkyl, halogen, cyano, 3-7 membered alicyclic alkyl or 4-8 membered alicyclic heterocyclic group, wherein the alicyclic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O, wherein the C 1-6 Alkyl, 3-7 membered aliphatic rings or 4-8 membered aliphatic heterocycles may be optionally surrounded by 0, 1, 2 or 3 Rs. 5 replace; R 3 Selected from cyano, C 1-6 Acyl group, C 1-6 alkylsulfonyl, -C(O)-NR a R b or R a Or R b Each is independently H or C 1-3 alkyl; R 3a Or R 3b Each is independently selected from H, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclic group is optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O; R 3c Selected from H, cyano, hydroxyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 alkylsulfonyl, C 2-6 The ester group, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace; R 4 Selected from halogen, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 5 Selected from halogens, hydroxyl groups, cyano groups, C 1-6 Acyl or C 1-6 alkylsulfonyl; R 6 Selected from oxo, cyano, hydroxyl, halogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Ester group, -C(O)-NRaRb, C 1-6 Acyl or C 1-6 alkylsulfonyl; R 7 Selected from cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, halogen, or oxo; The condition is that X is CH when A contains 3 N atoms; When A contains 2 N atoms, X is N, R 3 yes And R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2, or 3 heteroatoms selected from N, S, or O, and R 3c It is not H or cyano.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: A is a five-membered heteroaryl group containing 2 or 3 N atoms; X is N or CH; Y is a single bond, O, S, NH, or NRy, and Ry is C. 1-6 alkyl; R 1 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 5-6-membered heteroaryl, wherein C 3-6 Cycloalkyl or 5-6 heteroaryl groups are optionally halogenated or C 1-3 One or more substitutions in alkyl groups; R 2 It is C 1-6 Alkyl, halogen, cyano, 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle, wherein the aliphatic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O, and the 3-7 membered aliphatic ring or 4-8 membered aliphatic heterocycle is optionally surrounded by 1, 2 or 3 R atoms. 5 replace; R 3 It is cyano, C 1-6 Acyl group, C 1-6 alkylsulfonyl, -C(O)-NRaRb or Ra or Rb are each independently selected from H or C. 1-3 alkyl; R 3a Or R 3b Each group is independently selected from H, cyano, hydroxyl, and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O; R 3c It is H, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkylsulfonyl, C 2-6 The ester group, 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-6 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-7 membered aliphatic ring, 4-6 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace; R 4 It is halogen, cyano, C 1-6 Alkyl or halogenated C 1-6 alkyl; R 5 It is halogen, hydroxyl, cyano, C 1-6 Acyl or C 1-6 alkylsulfonyl; R 6 It is oxo, cyano, hydroxyl, halogen, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Ester group, -C(O)-NRaRb, C 1-6 Acyl or C 1-6 alkylsulfonyl; R 7 It is cyano, C 1-6 Alkyl or oxo; The condition is that X is CH when A contains 3 N atoms; When A contains 2 N atoms, X is N, R 3 yes And R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-7 membered aliphatic ring or a 4-8 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O, and in this case R 3c It is not H or cyano.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein: Y is a single bond, O, S, or NH; R 1 It is C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, the C 3-6 cycloalkyl groups may be halogenated or C 1-3 One or more substitutions in alkyl groups; R 2 It is C 1-3 Alkyl, halogen, cyano, 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle, wherein the aliphatic heterocycle contains one or two heteroatoms selected from N, S or O, and the 3-6 membered aliphatic ring or 4-6 membered aliphatic heterocycle is optionally surrounded by one, two or three R atoms. 5 replace; R 3 yes R 3a Or R 3b Each group is independently selected from H, cyano, hydroxyl, and C. 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted with one or more of halogen, cyano, hydroxyl, alkoxy, and amino groups; or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The substituted ring is a 3-6 membered aliphatic ring or a 4-7 membered aliphatic heterocycle, the aliphatic heterocycle containing 1, 2 or 3 heteroatoms selected from N, S or O; R 3c It is H, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkylsulfonyl, C 2-3 The ester group, 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl group, wherein the 4-5 membered aliphatic heterocycle or 5-6 membered heteroaryl group contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S, and wherein the 3-5 membered aliphatic ring, 4-5 membered aliphatic heterocycle, or 5-6 membered heteroaryl group is optionally surrounded by 1, 2, or 3 R atoms. 7 replace; R 4 It is halogen, cyano, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 5 It is a halogen, hydroxyl, cyano, formyl, acetyl, methanesulfonyl, or ethylsulfonyl group; R 6 It is an oxo, cyano, hydroxyl, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, methyl ester, ethyl ester, formyl, acetyl, methylsulfonyl, or ethylsulfonyl; R 7 It is cyano, C 1-3 Alkyl or oxo.

4. Compounds of formula (IIa) and (IIb) or their pharmaceutically acceptable salts: in, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 2; More preferably, the compound or its salt has the structural formula (II): Among them, R 1 R 2 R 3a R 3b R 4 As defined in claim 2.

5. Compounds of formula (Ⅲa) or pharmaceutically acceptable salts thereof: in, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 2, More preferably, the compound or its salt has the structural formula (III): Among them, R 1 R 2 R 3a R 3b R 4 As defined in claim 2.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is NH; R 1 Selected from C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl groups are optionally coated with halogens, C 1-3 Alkyl, C 1-3 Alkoxy or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group; The condition is that A contains 2 N atoms, X is N, and R... 1 It is an unsubstituted ethyl group, R 2 It is a cycloalkyl group, R 3 yes R 3c When it is a triazole group, R 3a Or R 3b Not both are methyl, and R 3a and R 3b It does not form a ring.

7. The compound of claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IV), formula (V), or formula (VI): in, Y, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 1 or 6.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (IVa): in, R 1 It is C 1-6 Alkyl; R 2 It is C 3-6 cycloalkyl; R 3a Or R 3b Each is C independently 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-6 cycloalkyl; R 4 It is C 1-6 Halogenated alkyl groups; Preferably, R 1 It is methyl or ethyl; R 2 It is cyclopropyl; R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are bonded to, they form a cyclopropyl group; R 4 It is trifluoromethyl.

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (Va): in, R 1 R 2 R 3a R 3b R 3c R 4 As defined in claim 7.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkynyl or C 3-6 cycloalkyl groups are optionally coated with halogens, C 1-3 Alkyl or C 1-3 One or more substitutions in the alkoxy group; R 2 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocyclic groups, wherein the aliphatic heterocycle contains 1, 2, or 3 heteroatoms selected from N, S, or O, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocyclic groups are optionally surrounded by 1, 2 or 3 R groups. 5 replace; R 3a Or R 3b Each is independently H or C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form a group that can optionally consist of 1, 2, or 3 R atoms. 6 The replaced ring, the ring being C 3-6 Cycloalkyl or 4-8 membered aliphatic heterocycles, wherein the aliphatic heterocycle contains 1, 2 or 3 heteroatoms selected from N, S or O; R 3c It is C 1-6 Alkyl or 5-6-membered heteroaryl, said heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from N, O or S, said heteroaryl being optionally surrounded by 1, 2 or 3 R atoms. 7 replace; R 4 It is C 1-6 Halogenated alkyl groups; R 5 It is either halogen or cyano; R 6 It is oxygenation; R 7 It is C 1-6 Alkyl or C 1-6 Alkylthio; Preferably, R 1 Selected from C 1-3 Alkyl, C 2-3 alkynyl or C 3-4 cycloalkyl, the C 1-3 Alkyl, C 2-3 alkynyl or C 3-4 The cycloalkyl group may optionally be substituted with one or more of a halogen or a methoxy group; R 2 Selected from methyl, cyclopropyl, oxetane, or tetrahydrofuranyl, wherein the methyl group is optionally surrounded by one R 5 replace; R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form an optional group of 2 R atoms. 6 The replaced ring, the ring being C 3-5 Cycloalkyl or tetrahydrothiophene group; R 3c It is a methyl or 5-6-membered heteroaryl group, wherein the heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N or S, and the heteroaryl group is optionally surrounded by one R 7 replace; R 5 It is cyano; R 6 It is oxygenation; R 7 It is methyl or ethyl thio.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (Vb): in, R 1 It is C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 cycloalkyl groups are optionally C 1-3 Alkyl or C 1-3 One or more substitutions in the alkoxy group; R 3a Or R 3b It is C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-5 cycloalkyl; R 3c It is a 5-membered heteroaryl group, wherein the heteroaryl group contains 1, 2 or 3 heteroatoms selected from N or S; Preferably, R 1 It is ethyl or cyclobutyl, wherein the cyclobutyl group is optionally substituted with methyl or methoxy; R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form a cyclopropyl group; R 3c yes 12. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIa): in, R 1 It is C 1-3 Alkyl; R 8 It is C 1-3 Halogenated alkyl groups; Preferably, R 1 It is methyl or ethyl; R 8 It is trifluoromethyl or difluoromethyl.

13. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VII): in, X or X 1 Each is either N or CH independently; R 1 It is C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 cycloalkyl groups are optionally halogenated or di(C) 1-3 One or more substitutions in alkyl)oxyphosphine group; R 3a Or R 3b It is C 1-6 Alkyl, or R 3a and R 3b Together with the atoms they are connected to, they form C 3-5 cycloalkyl; R 3c It can be chosen by 1 or 2 Rs. 7 Substituted triazole or tetraazole groups; R 7 Each is C independently 1-3 alkyl; Preferably, R 3c yes 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIIa) or (VIIb): in, R 1 R 3a R 3b R 3c As defined in claim 13.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (VIIc) or formula (VIId): in, R 1 It is C 1-6 Alkyl or C 3-6 cycloalkyl, the C 1-6 Alkyl or C 3-6 The cycloalkyl group may optionally be substituted with one, two or three halogens; R 3c It is optional to be one R 7 Substituted triazole or tetraazole groups; R 7 It is C 1-3 alkyl; Preferably, R 1 C can be arbitrarily replaced by 1, 2, or 3 Fs. 1-3 Alkyl or cyclopropyl; R 3c yes R 7 It is a methyl group.

16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein: R1 is ethyl or cyclopropyl; R 3a Or R 3b It is methyl, or R 3a and R 3b Together with the atoms they are connected to, they form a cyclopropyl group; R 3c yes 17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

18. A pharmaceutical composition comprising a compound as described in any of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, or the pharmaceutical composition of claim 18, in the preparation of a medicament for treating LRRK2 receptor-related conditions.

20. The use according to claim 19, wherein the condition is a neurodegenerative disease, an immune-inflammatory disease, a tumor, or glaucoma.

21. The use according to claim 19, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar atrophy, Friedreich ataxia, Pick's disease, Lewy body dementia, dystonia, amyotrophic lateral sclerosis, neuroinflammation, progressive supranuclear palsy, and frontotemporal dementia.

22. The use according to claim 19, wherein the immune-inflammatory related disease is selected from inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, ankylosing spondylitis, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura, Evans syndrome, vasculitis, bullous skin diseases, type I diabetes, Sjögren's syndrome, Dervous disease, and inflammatory myopathy.

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